Electrokinetic Delivery System for Self-Administration of Medicaments and Methods Therefor

ABSTRACT

The invention relates to systems and methods for treating a fungal infection of the nail of an individual. In various embodiments, the methods include applying a device to at least one nail of the individual that is infected by a fungus. In various embodiments, the devices include at least one active electrode and at least one counter electrode, with the at least one counter electrode in contact with the individual.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 11/373,301, filed Mar. 13, 2006, which is a division of U.S.patent application Ser. No. 10/724,160, filed Dec. 1, 2003, now U.S.Pat. No. 7,016,724, which is a division of U.S. patent application Ser.No. 10/117,346, filed on Apr. 8, 2002, now U.S. Pat. No. 6,792,306,which is a continuation-in-part of both U.S. patent application Ser. No.09/584,138, filed on May 31, 2000, now U.S. Pat. No. 6,477,410, and ofU.S. patent application Ser. No. 09/523,217, filed Mar. 10, 2000, nowU.S. Pat. No. 6,553,253, which claims priority from U.S. ProvisionalApplication No. 60/123,934, filed Mar. 12, 1999, all of which areincorporated by reference herein as if each is being set forth herein inits entirety.

BACKGROUND OF THE INVENTION

Electrokinetic delivery of medicaments for applying medication locallythrough an individual's skin is known. One type of electrokineticdelivery mechanism is iontophoresis, i.e., the application of anelectric field to the skin to enhance the skin's permeability and todeliver various ionic agents, e.g., ions of soluble salts or otherdrugs. In certain situations, iontophoretic transdermal ortransmucocutaneous delivery techniques have obviated the need forhypodermic injection for many medicaments, thereby eliminating theconcomitant problem of trauma, pain and risk of infection to theindividual. Other types of electrokinetic delivery mechanisms includeelectroosmosis, electroporation, electromigration, electrophoresis andendosmose, any or all of which are generally known as electrotransport,electromolecular transport or iontophoretic methods. The electrokineticdelivery mechanism may also be accompanied by ultrasonic vibration tofurther facilitate electrokinetic transport of the substance, e.g., byopening pores in the skin. Ultrasound may be employed in a number ofways such as (i) traditional piezoelectric elements, (ii) ApplicationSpecific Integrated Circuits (ASIC) with ultrasound transmitter built inor (iii) by thin foil sheets with incorporated piezoelectric dipoleelements.

There are several difficulties with electrokinetic delivery ofsubstances such as medicaments. One is the heretofore need for somewhatcumbersome, bulky and costly equipment which oftentimes requires thepresence of an individual at a doctor's office or treatment center anduse of medical professionals to administer the medicament. Private,self-administration of medicaments or for diagnostic application by theindividual at non-medical or non-professional facilities is highlydesirable. Also, an easily transportable apparatus for electrokineticdelivery of medication, for example, a lightweight, compact portabledevice useful with an applicator packaged as a single or unit dosageapplicator, appears ideal as a patient/consumer friendlyself-administration system appropriate for many circumstances.

BRIEF SUMMARY OF THE INVENTION

The invention includes methods of treating a fungal infection of a nailof an individual. In various embodiments, the method includes applying adevice to at least one nail of an individual that is infected by afungus. In some embodiments, the device includes at least one activeelectrode and at least one counter electrode, with the at least onecounter electrode being in contact with the individual. The device isconnected to at least one power source. In various embodiments, ananti-fungal medicament is disposed between the at least one activeelectrode and the at least one nail of the individual infected by afungus and a an electrical current is provided from the power source tothe at least one active electrode to facilitate delivery of theanti-fungal medicament into the region of the at least one nail.

In one embodiment, the medicament is contained within a pad. In anotherembodiment, the medicament includes a conductive fluid. In yet anotherembodiment, the nail is a toenail. In a further embodiment, themedicament is delivered directly into the nail bed. In yet anotherembodiment, the medicament is delivered into the nail bed and thesurrounding nail tissue.

The invention further includes a device for delivery of a substance to atreatment site on an individual. In one embodiment, the device includes:a power supply; an applicator including a first electrode and a pad forcontaining a substance, wherein the first electrode is connected to thepower supply and the pad is positioned on a first side of the applicatorwith the first electrode overlying the pad; and a second electrodeconnected to the power supply. In some embodiments, upon application ofthe applicator against the treatment site and the second electrode incontact with a portion of the individual's body, an electrical circuitis completed between the first electrode through the treatment site, theportion of the individual's body, and the second electrode forelectrokinetically driving the substance into the treatment site.

In one embodiment, the substance is an anti-fungal agent. In anotherembodiment, the substance comprises a conductive fluid. In someembodiments, the treatment site is a nail. In certain embodiments, thenail is a toenail. In yet another embodiment, the medicament isdelivered directly into the nail bed. In a further embodiment, themedicament is delivered into the nail bed and the surrounding nailtissue.

The invention also includes a system for delivering a substance to aninfected nail of an individual. In one embodiment, the system includes:a power source and a device connected to the power source. In someembodiments, the device comprises at least one active electrode and atleast one counter electrode, wherein the at least one counter electrodeis in contact with the individual and a medicament is disposed betweenthe at least one active electrode of the device and the infected nail ofthe individual. In various embodiments, an electrical current isprovided from the power source to the at least one active electrode toelectrokinetically drive the medicament into the region of the infectednail.

In one embodiment, the substance is an anti-fungal agent. In anotherembodiment, the substance is contained within a pad. In yet anotherembodiment, the substance comprises a conductive fluid. In a furtherembodiment, the nail is a toenail. In yet another embodiment, thesubstance is delivered directly into the nail bed. In yet anotherembodiment, the substance is delivered into the nail bed and thesurrounding nail tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating the invention, there are depicted in thedrawings certain embodiments of the invention. However, the invention isnot limited to the precise arrangements and instrumentalities of theembodiments depicted in the drawings.

FIG. 1 is a schematic illustration of an electrokinetic medicamentdelivery device for use with an applicator in accordance with thepresent invention;

FIG. 2 is a perspective view of the device with the applicator appliedthereto;

FIG. 2A is a view similar to FIG. 2 of a modified form of the device andapplicator;

FIG. 3 is a perspective view illustrating the device and applicator inuse by an individual and being applied to a lesion on the individual'schin;

FIG. 4 is a plan view of an applicator from the skin side;

FIG. 5 is a plan view of the applicator from the device side;

FIG. 6 is an exploded side elevational view illustrating the variousparts of the applicator;

FIGS. 7 and 8 are views of the applicator pad, respectively,illustrating an encapsulated medicament and a combination ofencapsulated medicament and hydration fluid within the applicator pad;

FIG. 9 is a perspective view of a splint-like strip forming aself-contained applicator electrode in accordance with a furtherembodiment of the present invention;

FIG. 9A is a view similar to FIG. 9 illustrating a further form of thestrip of FIG. 9;

FIG. 10 is a schematic view of an electrical circuit for use with theapplicator electrode of FIG. 9;

FIGS. 11A, 11B and 11C are schematic representations of a self-containedapplicator illustrating the layers of the applicator within a packagingmaterial;

FIG. 12 is a schematic representation of an applicator in accordancewith a further embodiment of the present invention;

FIGS. 13 and 14 are preferred forms of the applicator of FIG. 12 with anencapsulated medicament illustrated in FIG. 13 and encapsulatedmedicament and hydrating fluid illustrated in FIG. 14;

FIG. 15 is a side elevational view of a further form of the presentinvention;

FIG. 16 is an exploded schematic view of a still further form ofapplicator electrode in accordance with the present invention;

FIG. 17 is a fragmentary view of the applicator of FIG. 16 applied tothe end of a device;

FIG. 18 is an illustration of a hands' free electrokinetic medicamentdelivery device;

FIG. 19 is a schematic illustration of a still further hands' freeelectrokinetic delivery device according to the present invention;

FIG. 20 is a perspective view of a further form of an applicator,illustrated with its packaging, for use with an electrokinetic deliverydevice;

FIG. 21 is a view of the applicator of FIG. 20 without its packaging;

FIG. 22 is a schematic illustration of the applicator of FIGS. 20 and 21applied to the electrokinetic device;

FIG. 23 is a perspective view of the device with the applicator appliedready for use;

FIG. 24 is a schematic representation of an alarm system formisplacement of the probe;

FIG. 25 is a schematic illustration of an electrokinetic applicator inthe form of a sock for treatment of fungal infestations between thetoes;

FIG. 26 is a view similar to FIG. 25 illustrating an electrokineticapplicator for treatment of a nail bed fungal infestation;

FIG. 27 is a schematic representation of a device for electrokineticallytreating a fungal infestation of the nail beds of an individual'sfingers;

FIG. 28 is a schematic illustration of the electronics and thimble padapplicator of the device of FIG. 27;

FIG. 29 is a schematic representation of a device for electrokineticocular treatment;

FIG. 30 is a side elevational view of an ocular applicator according tothis aspect of the invention; and

FIG. 31 is a planar view of the ocular applicator illustrating themulti-channel conductors;

FIG. 32 is a graph of risk current (RMS) in microamperes versusfrequency showing the risk current limits based on fibrillatorythresholds.

FIG. 33 shows an iontophoretic delivery system 300 in accordance with anembodiment of the present invention.

FIG. 34 shows a block diagram of electrical circuit elements of anembodiment of the present invention.

FIG. 35 shows a hand-held device with internal layout of electric andelectronic elements;

FIG. 36 is a schematic representation of a manner of applying anelectrokinetic delivery device according to a preferred embodiment ofthe present invention to a treatment site;

FIG. 37 is an enlarged fragmentary exploded perspective viewillustrating the device hereof;

FIG. 38 is a perspective view of a preferred embodiment of the device asviewed from its underside;

FIG. 39 is an elevational view of the device at a proximal end thereof;

FIG. 40 is a top plan view of the device;

FIG. 41 is a side elevational view thereof;

FIG. 42 is an exploded perspective view of a medicated cartridge and theapplication head to which the cartridge is applied;

FIG. 43 is a side elevational view of a portion of an applicator headand substrate in accordance with another embodiment hereof;

FIGS. 44 and 45 are disassembled and assembled perspective views of anelectrokinetic delivery device according to another embodiment hereof;

FIG. 46 is a block diagram of an example electrical circuit for thedevice hereof;

FIG. 47 is a schematic of an example electrical circuit for the devicehereof;

FIG. 48 is a perspective view of a face mask electrokinetic deliverydevice according to a further preferred embodiment hereof;

FIG. 49 is a view similar to FIG. 48 illustrating a further form of facemask;

FIG. 50 is a side elevational view of a generally ring-shapedelectrokinetic delivery device according to a still further preferredembodiment;

FIG. 51 is a perspective view thereof;

FIGS. 52 and 53 are a bottom view and a side perspective view,respectively, of a patch applicator;

FIGS. 54A and 54B are flow charts illustrating an example operation ofthe device of FIG. 37.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to systems and methods for treating a fungalinfection of the nail of an individual. In various embodiments, themethods include applying a device to at least one nail of the individualthat is infected by a fungus. In various embodiments, the devicesinclude at least one active electrode and at least one counterelectrode, with the at least one counter electrode in contact with theindividual.

A. Electrokinetic Delivery of Medicaments

In accordance with a preferred embodiment of the present invention,there is provided a portable, self-contained, hand-held lightweight,compact and wireless electrokinetic device for delivering or removing asubstance, e.g., a medicament, and a unit dosage substance applicatorfor use with the device for the self-administration of a medicament tothe skin. By the term substance is meant a medicament as well as naturalor homeopathic products that may be outside the definition ofmedicament, e.g., inks and pigments for tattoos, and more generallyincludes any substance capable of electrokinetic transport through skinor mucocutaneous membrane, e.g., into a treatment site or from a site,e.g., for diagnostic purposes. The majority of applications using thepresent invention are for applying medicaments to treatment sites andtherefore the term medicament is used in lieu of the term substancethroughout this specification. By medicament is meant any chemical orbiologic that may be used on or administered to humans or animals as anaid in the diagnosis, treatment or prevention of disease or otherabnormal or cosmetic condition or for the relief of pain or to control,diagnose or improve any physiologic or pathologic condition.

Major therapeutic classes include but are not limited to, ACEinhibitors, such as ranitidine, anti-infectives such as antibacterials,antivirals and antimicrobials, vasodilators, including general,coronary, peripheral and cerebral, adrenocortical steroids,alpha-adrenergic agonists, alpha-adrenergic antagonists, selectivealpha-two-adrenergic agonists, analgesics, and analgesic combinations,androgens, local and general anesthetics, antiaddictive agents,antiandrogens, antiarrhythmic agents, antiasthmatic agents,anticholinergic agents, anticholinesterase agents, xanthine derivatives,cardiovasculars including calcium channel blockers such as nifedipine,beta agonists such as dobutamine and ritodine, anticoagulants, includingheparin, anticonvulsants, antidiabetic agents, antidiarrheal agents,antidiuretic, antiemetic and prokinetic agents, antiepileptic agents,antiestrogens, antihypertensives, such as atenolol, antimigraine agents,antimotionsickness preparations such as scopolamine, ondansetron,meclizine, antinausants, antimuscarinic agents, antiprurtics,antipsychotics, antipyretics, antispasmodics such as gastrointestinaland urinary, antineoplastic agents, antiparasitic agents,anti-Parkinson's agents, antiplatelet agents, antiprogestins,antithyroid agents, antitussives, atypical antidepressants,azaspirodecanediones, barbituates, benzodiazepines, benzothiadiazides,beta blockers, antiarrythmics beta-adrenergic agonists, beta-adrenergicantagonists, selective beta-one-adrenergic antagonists, selectivebeta-two-adreneric antagonists, bile salts, medicaments affecting volumeand composition of body fluids, butyrophenones, agents affectingcalcification, catecholamines and sympathomimetics, cholergic agonists,cholinesterase reactivators, dermatological medicaments,diphenylbutylpiperines, diuretics, ergot alkaloids, estrogens,ganglionic blocking agents, ganglionic stimulating agents, hydantoins,agents for control of gastric acidity, and treatment of peptic ulcers,hematopoitic agents, hisamines, histamine antagonists,5-hydroxytryptamine antagonists, hyperlipoproteinemia medicaments,hypnotics and sedatives, tranquilizers, hormones, including pituitaryhormones such as HGH, HMG, HCG, desmopressin acetate and the like;follicle luteolds, α-ANF, growth factor releasing factor (GFRF), β-MSH,somatostatin, bradykinin, somatotropin, platelet-derived growth factor,asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionicgonadotropin, corticotropin (ACTH), epidermal growth factor,erythropoietin, epoprostenol (platelet aggregation inhibitor), folliclestimulating hormone, glucagons, hirulog, hyaluronidase, insulin likegrowth factors, m[a]enotropins (urofollitropin (FSH) and LH), oxytocin,streptokinase, tissue plasminogen activator, urokinase, ACTH analogs,ANP, ANP clearance inhibitors, angiotensin II antagonists, antidiuretichormone agonists, antidiuretic hormone antagonists, bradykininantagonists, CD4, ceredase, enkephalins, FAB fragments, IgE peptidesuppressors, IGF-1, neurotrophic factors, colony stimulating factors,parathyroid hormone agonists, parathyroid hormone antagonists,pentigetide, protein C, protein S, rennin inhibitors, thymosin alpha-1,thrombolytics, TNF, vaccines, alpha-1 antitrypsin (recombinant), andTGF-beta, immunosuppressives, parasympatholytics, parasympathomimetics,psychostimulants, laxatives, methylxanthines, monomine oxidaseinhibitors, neuromuscular blocking agents, organic nitrates, opoidanalgesics and antagonists, pancreatic enzymes, phenothiazines,progestins, prostaglandins, e.g., alprostadil, agents for treatment ofpsychiatric disorders, sodium channel blockers, medicaments forspasticity and acute muscle spasms, e.g., muscle relaxants,succinimides, thioxanthines, thrombolytic agents, thyroid agents,tricyclic antidepressants, inhibitors of tubular transport of organiccompounds, uterine motility affecting agents, and the like.

Representative medicaments, their analogs and derivatives thereof,included by way of example and not for purposes of limitation, areinterferons, e.g., α-2b interferon, amphotericin β, angiopeptin,baclofen, bepridil, buserelin, buspirone, calcitonin, ciclopirox,olamine, copper, cyclosporin, zinc, tropisetron, vapreotide,vasopressin, vasopressin antagonist analogs, verapamil, warfarin,zacopride, zotasetron, cromolyn sodium, diltiazem, felodipine,isradipine, nicardipine, nifedipine, nimodipine, nitredipine, verapamil,isoproterenol, carterolol, labetalol, levobunolol, minoxidil, nadolol,penbuterol, pindolol, propranolol, sotalol, timolol, acebutolol,betaxolol, esmolol, metaproterenol, pirbuterol, ritodrine, terbutaline,alclometasone, aldosterone, amcinonide, beclomethasone, dipropionate,betamethasone, clobetasol, clocortolone, cortisol, cortisone,corticosterone, desonide, desoximetasone, 11-desoxycortiosterone,11-desoxycortisol, diflorasone, fludrocortisone, flunisolide,fluocinolone, fluocinonide, fluorometholone, flurandrenolide, G-CSF,GM-CSF, M-CSF, GHRF, GHRH, gonadorelin, goserlin, granisetron,halcinonide, hydrocortisone, indomethacin, insulinotropin, interleukins,e.g., interleukin-2, isosorbide dinitrate, leuprolide, lisinopril, LHRH,LHRH analogs such as buserlin and leuprolide, octreotide, endorphin,TRH, NT-36(-[[(s)-4-oxo-2-azetidinyl]carbonyl]-histidyl-L-prolinamide),liprecin, LMW heparin, i.e., enoxaparin, melatonin, medrysone,6α-methylprednisolone, mometasone, paramethasone, prednisolone,prednisone, tetrahydrocortisol, trimcinolone, benoxinate, benzocaine,bupivacaine, chloroprocaine, dibucaine, dyclonine, etidocaine,mepivacaine, pramoxine, procaine, proparacaine, tetracaine, chloroform,cloned, cycloproane, desflurane, diethyl ether, droperidol, enflurane,etomidate, halothane, isoflurane, ketamine, hydrochloride, meperidine,methohexital, methoxylflurane, nitrogylcerine, propofol, sevoflurane,thiamyal, thiopental, acetaminophen, allopurinol, apazone, aspirin,auranofin, aurothioglucose, colchiine, diclofenac, diflunisal, etodolac,fenoprofen, flurbiprofen, gold sodium thiomalate, ibuprofen,indomethacin, ketoprofen, meclofenamate, mefenanic acid, meselamine,methyl salicylate, nabumetone, naproxen, oxyphenbutazone, phenacetin,phenylbutazone, piroxicam, salicylamide, salicylate, salicylic acid,salsalate, sulfasalazine, sulindae, tometin, acetophenazine,chlorpromazine, fluphenazine, mesoridazine, perphenazine, thioridazine,triflurperazine, triflupromazine, disopyramide, encamide, flecinide,indecamide, mexiletine, moricizine, phenyloin, procainamide,propafenone, quinidine, tocaine, cisapride, domperdone, dronabinol,haloperidol, metoclopramide, nabilone, nicotine, prochlorperazine,promethazine, thiethylperazine, trimethobenzamide, buprenorphine,butorphanol, codeine, dezocine, diphenoxylate, drocode, doxazosin,hydrocodone, hydromorphone, levallorphan, levorphanol, lopermide,meptazinol, methadone, nalbuphine, nalmefene, naloxone, naltrexone,oxybutynin, oxycodone, oxymorphone, pentazocine, propoxyphene,isosobide, dinitrate, nitroglycerin, theophylline, phenylephrine,ephedrine, pilocarpine, furosemide, tetracycline, chlorpheniramine,ketorolac, bromocriptine, guanabenz, prazisin, doxazosin, and flufenamicacid.

Also, representative of medicaments, their analogs and derivativesthereof, which may be delivered are benzodiazepines such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, flumazenil, flurazepam, halazepam, lorazepam,midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam,temazepam, triazolam and the like; antimuscarinic medicaments such asanistropine, atropine, clininium, cyclopentolate, dicyclomine,flavoxate, glycopyrrolate, hexocyclium, homatropine, ipratropium,isopropamide, mepenzolate, methantheline, oxyphencyclimine, pirenzepine,propantheline, scopolamine, telenzepine, tridihexethyl, tropicamide, andthe like; an estrogen such as chlorotrianisene, siethylstilbestrol,methyl estradiol, estrone, estrone sodium sulfate, estropipate,mestranol, quinestrol, sodium equilin sulfate, 17β-estradiol (orestradiol), semi-synthetic estrogen derivatives such as esters ofnatural estrogen, such as estradiol-17β-enanthate,estradiol-17β-valerate, estradiol-3-benzoate, estradiol-17β-undecenoate,estradiol 16,17-hemisuccinate or estradiol-17β-cypionate, and the17-alkylated estrogens, such as ethinyl estradiol, ethinylestradiol-3-isopropylsulphonate, and the like; an androgen such asdanazol, fluoxymestetone, methandrostenolone, methyltestosterone,nadrolone decanoate, nandrolone, phenpropionate, oxandrolone,oxymetholone, stanozolol, testolactone, testosterone, testosteronecypionate, testosterone enanthate, testosterone propionate, and thelike; or a progestin such as ethynodiol diacetate, gestodene,hydroxyprogesterone caproate, levonnorgestrel, medroxyprogesteroneacetate, megestrol acetate, norethindrone, norethindrone acetate,norethynodrel, norgestrel, progesterone and the like.

For example, by employing the device and the applicator hereof, it ispossible to electrokinetically deliver medicaments such as anti-virals,for treating human papilloma virus, (HPV), e.g., warts (common, flat,plantar and genital), examples of which are Imiquimod® sold as Aldara™by 3M for genital warts, a type (HPV), Acyclovir®, sodium salicylate,tretinion, benzoyl peroxide, bleomycin, interferons, Podocon-25, OTCproducts such as Wart Off by Pfizer and Compound W by MedTech oranti-picornavirus class substances, e.g., Pleconaril, to treat coughsand colds, anti-inflammatory medicaments such as dexamethasone andanti-bacterial agents, proteins, as well as steroids and salts thereof,non-steroidal anti-inflammatory drugs (NSAIDs), and salts thereof,hormones, cytokines, viruses, bacteria, DNA, RNA, (and fragments ofboth), antihistamines, oligonuceotides, anti-proliferative agents(cancer), specifically 5-fluorouracil (5-FU) and cisplatin, Efudex, or acombination of 5-FU and soviudine, anti-angiogenics such as thalidomide,antibiotics, peptides and peptidomimetics and assemblages of aminoacids, phenols and polyphenols, an example of which is PolyphenonE andcosmetic agents, such as retinoids, e.g., hyaluronic acid, vitaminsand/or water, skin bulking agents, e.g., collagen, reactive monomerswhich may polymerize under the skin in non aqueous carriers and beactivated by water, botulinum toxins, e.g. botox, bleaching agents,e.g., Eldopaque 4% by ICN Pharmaceuticals, or a combination ofKetorolac, hydroquinone 4%, Glycolic Acid, lactic acid with suitablevehicle and anesthetics, such as lidocaine, xylocalne, prontocaine,prilocalne, fetanyl, remifentanil, sufentanil, alfentanil, novocaine,procaine, morphine HCL and EMLA either in stand alone fashion or with avasodilator such as epinephrine. Also, medicaments which inhibit fusionbetween the plasma membrane and viruses and other adventitious agents toprevent entry by viruses and/or other adventitious agents into cells mayalso be electrokinetically delivered, e.g., behenyl alcohols such asn-disocanol, its analogs or derivatives. Hair growth may be stimulatedby Propecia (finasteride), minoxidil, blocking antidihydrotestosteronesor antidihydroestrogens. Hair removal may be accomplished by dyeing thehair and or hair root to facilitate removal by laser means or byelectrokinetically using, e.g., dihydrotestostersone or dihydroandrogensor dihydroestrogens. Using pigments, tattoos, either temporary(reversible) or permanent may be applied to a treatment site and tattooswhen permanent may be removed using suitable medicaments and the instantinvention. Water soluble dyes and decals or templates may be employed inconjunction with the device and applicators. Prostate conditions e.g.,prostatitis may be treated with antineoplastics. Additionally, thediagnostic sweat test for cystic fibrosis using pilocarpine, peripheralvascular disease using vasodilators, eye (corneal) treatment usingflorescein, acne treatments with one or more steroids, NSAIDs, such asketorolac or medicaments such as Benzamycin, benzoyl perixode, cleocin,T-Stat, over the counter (OTC) products two examples of which areClearasil and Benzac or Accutane, tazarotene sold as Tazorac, adapalenesold as Differin by Allergan and Galderma respectfully or azelaic acid,a topical cream also sold by Allergan, erythromycin as well ascombinations of such medicaments may be electrokinetically delivered.Psoriasis may be treated with an antimetabolite, retinoids, syntheticvitamin D, i.e., calciprotriene, cyclosporin A (CSA), Aristocort, fromLederle, anthrax-derm, by Dermik, methotrexate, cortisone like compoundspsoralen or anthalin. Eczema and contact or atopic dermatitis may betreated with corticosteroids or antihistamines. Spider veins may betreated with antiangiogenics, or coagulants (clotting factors orfragmented cellulose polymer). Fluoride treatment of exposed single sitehypersensitive dentin may be performed with this device and applicatorsystem. Canker sores and RAS may be treated with, e.g., benzoin orsodium fluoride. Post herpetic neuralgia may be treated with localanesthetics mentioned throughout this disclosure and/or with antivirals,e.g., Acyclovir or combinations of anesthetic and antiviral. Erectiledysfunction may also be treated (transcutaneously at site of concern)using prostaglandins such as PGE or alprostadil, nitroglycerin, and thelike or papaverine, yohimbine and the like or sildenafil citrate, i.e.,viagra, or apomorphine HCl. Other diagnostic uses i.e., removal orextraction of animal or human bodily material, e.g., fluids, versusdelivery of medicament include as examples, allergy screening, e.g.,using an electrode mounted array of antigens, with amultiplexed-multi-channel application electrode, glucose monitoring anddrug testing using electrode mounted specific binders (binder assay)combined with reverse iontophoretic plasma extraction. As a furtherdiagnostic application, body material such as fluids can be extractedinto a pad on the electrokinetic device, for example, by reverseiontophoresis. Wounds such as scrapes, cuts, burns, plant allergies,punctures and insect bites or stings can be treated with antihistamines,antibiotics, anti-infectives such as bactracin, Diprolene, topicalsteroids, and the like, aloe or aloe containing products or OTC productssuch as Ambesol, Lanocaine and the like, other wound healing agents,such as epidermoid derived growth factors as well as peptides thatmodulate the inflammatory response and modulators of collagen depositionand modeling as well as other wound healing agents allelectrokinetically delivered. Pre-treatment may also includedesensitizing agents such as the aforementioned analgesics or salicylicacid. Pruritis, dry skin and keratosis may also be treated using,cortisones and the like, Benadryl itch creme, Lazer creme or EMLA andthe like. Actinic keratoses may be treated by electrokinetic delivery ofaminolevulinic acid as well as other established antimetabolite agentssuch as methotraxate, 3% DICLOFENAC IN 2.5% hyaluronic acid, 5FU, 5FUand isotretinion, and the like. Bursitis or mild arthritis may betreated with magnesium sulfate or Dororac from Genderm.

A particular use of the device and applicator hereof is the delivery ofAcyclovir® and derivatives and analogs thereof for treatment ofrecurrent herpetic symptoms, including lesions (oral or genital) andvaricella zoster i.e., shingles. Other anti-herpetic medicaments capableof electrokinetic delivery in accordance with the present invention are5-iodo-2 deoxyuridine (IUDR), cytosine arabinoside (Ara-C), adeninearabinoside (Ara-A), also known as vidarabine, adenine arabinosidemonophosphate (Ara-AMP), arabinofuranosyl hypoxanthine (Ara-Hx),phosphonoacetic acid (PAA), thymine arabinoside (Ara-T), 5′-amino-T,5′-dideoxy-5-iodouridine (AIU),1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl) uracil (BV-ara-U), alsoknown as sorivudine, 1-beta-D-arabinofuranosyl-E-5(2-chlorovinyl)uracil(CV-ara-U), two halogenated deoxytidines (BrCdR and ICdR),bromovinyldeoxyuridine (BVDU), trifluorothymidin and Penciclovir®, itsprodrug, Famciclovir® and analogs and derivatives thereof, e.g.,penciclovir. Most if not all topical agents including both Acyclovir®and IUDR have demonstrated only limited efficacy when applied topicallyto herpetic lesions, or pre-lesion stage sites including prodomal stageskin sites. However, demonstrably improved clinical results have beenachieved when applied electrokinetically, e.g., electrophoretically, totreatment sites. Combinations may also be used including but not limitedto IUDR and DMSO. By a treatment site is meant a target tissue, e.g., adiseased tissue or diagnostic site for extraction of a substance,underlying or exposed through or on a human individual or lower animal'sskin or mucocutaneous membrane including, the eye and also including,but not limited to body cavity and canal sites such as mouth, ear, nose,vagina, and rectum. Some embodiments would not be appropriate for humaninfants and lower animals and human application to the animal wouldobviously replace self-application.

In a first aspect of the present invention, an individual may privatelyself-administer the medicament by employing the self-powered hand-helddevice to electrokinetically drive the medicament from an applicatorinto the treatment site, e.g., through the skin or mucocutaneousmembrane to a diseased tissue. Preferably, a low-cost throwawaysingle-use applicator is used to facilitate the flow of medicament intothe skin under the influence of the electromotive force supplied to themedicament contained in the applicator by the self-powered hand-heldwireless device. The hand-held device is preferably lightweight,compact, inexpensive and portable and comprises a housing configured forself-manipulation and containing a power source, for example, a battery,connected through first and second terminals and suitable electronics,including a current driver and voltage multiplier, with active andground electrodes. The active electrode is preferably mounted on the endof the device to facilitate manipulation of the device so that theactive electrode may engage the applicator against the skin ormucocutaneous membrane. The second terminal of the power source isconnected with the ground electrode, i.e., a tactile electrode, on thesurface of the device for electrical contact with a second skin site,i.e., a portion of the individual's hand engaging and manipulating thedevice. By self-manipulation is meant that the individual can engage thedevice in one hand or a portion thereof and freely orient the device toengage the active electrode of the device through the applicator ordirectly through medicament against the skin or mucocutaneous membranegenerally wherever the treatment site is located and irrespective ofwhether an applicator is used and, if used, irrespective of whether theapplicator is attached to the device or to the individual's skin ormucocutaneous membrane or interposed therebetween with the devicesubsequently applied to the applicator.

It will be appreciated that the metal portions of any electrodeconstruction may be of any of a variety of metals or metallic films,foils, screens, deposits, mesh, paints including but not limited toaluminum, carbon, gold, platinum, silver, silver chloride, copper orsteel, specifically surgical or similar fine grade steel, titanium, zincor alloys of the aforementioned materials. These metal materials mayalso be used as a component of an electrode with a plastic base, form orfoundation such as Mylar and the like. It is also possible that if theactive and ground electrodes are of dissimilar metals or have differenthalf cell reactions the device may generate part or all of itselectrical power by this galvanic couple system of which numeroussystems are well known in the art and require no further description. Attimes when hydration, ancillary or otherwise may be required,surfactants to facilitate the rate of hydration, i.e., wetting action,may be employed in, on or about the medicament applicator electrode withmaterials such as the surfactant Tween 20 or 85, made by ICI America,Neodol 91-6, from Shell Chemical Co., Terigol 15-S-7 from Union Carbide,Pluronic Poloxamer F68 or F127 from BASF or Duponol C or XL made byDupont Chemical Corp or isopropyl myristate.

In a preferred embodiment employing an applicator, the applicatorpreferably comprises a substrate having a reservoir, e.g., anopen-cellular structure, for containing a medicament. This preferredopen cellular or porous portion forms a minimum barrier to movement ofmedicament molecules under the influence of the applied current totransport the medicament molecules into the skin or mucocutaneousmembrane. The applicator thus forms an electrode for application to thetreatment site, e.g., an individual's skin and is preferably applied tothe device prior to application of the device and attached applicator tothe site. It will be appreciated, however, that the applicator electrodecan be applied directly to or adjacent to the treatment site, e.g., byusing an adhesive, prior to applying the device to the applicator. Tosecure the applicator electrode to the device prior to application tothe treatment site, an adhesive is preferably employed, although othertypes of securement may be used, such as complementary hook-and-loopfasteners, tabs, post and hole, magnets or the like. It will also beappreciated that an electrical circuit is completed through the activeelectrode of the device, the applicator electrode and the treatment sitefor return through the individual's skin in electrical contact with theground electrode of the device upon application of the device andapplicator electrode to the treatment site. Thus, by grasping the devicewith the individual's hand or finger in contact with the tactileelectrode, an electrical circuit is completed from the device throughthe applicator electrode, the treatment site, the individual's torso,arm and hand and the tactile electrode. To facilitate completion of theelectrical circuit, the applicator electrode may have a portion, whichoverlies the tactile electrode to facilitate the flow of electricalcurrent. For example, the applicator portion overlying the tactileelectrode may be open cellular or porous and may contain an electricallyconductive material, e.g., hydrogel. When this applicator substrateportion is pressed against the tactile electrode, electrical contactbetween the tactile electrode and the individual's skin is facilitated.Auxiliary hydration, e.g., wetting the fingers, the material or thetactile electrode may be employed to further facilitate closure of thecurrent loop in any or all applicator or device embodiments. Thehydrogel may also have adhesive properties or may contain an adhesiveand thereby serve or additionally serve as a mechanism for releasablysecuring the applicator to the device.

The medicament may be applied to the applicator by the user just priorto use. Alternatively, the medicament can be prepackaged as a unit dosein the applicator electrode. The medicament also may take many forms,for example, the medicament may be formulated as a liquid, a gel, anointment, a dry powder, a lotion, a foam, a solution or a cream.Depending upon the nature of the medicament, it may also be electricallyconductive per se, or require ancillary substances to transport themedicament, e.g., an electrically conductive substance such as water orvery weak trace saline to provide the necessary electrical conductivity.The applicator preferably includes a porous or open multi-cellular padto which medicament can be supplied by the user just prior to use or inwhich the medicament may be prepackaged. Where the medicament is notsufficiently electrically conductive per se, or is not part of ahydrophilic formulation, the user may hydrate the pad of the applicatorto render the medicament transportable by the electromotive force of theelectrical current flowing through the pad. Preferably, the applicatoris releasably secured, e.g., by adhesive, to the device. Alternatively,the applicator can be applied directly to the skin or mucocutaneousmembrane on or surrounding the treatment site, for example, by employinga releasable adhesive or the inherent tack of the substance includedwith the applicator electrode. In either mode of use, when the device,applicator pad and treatment site lie in series contact with one anotherand the circuit is completed through the individual's skin, electricalcurrent flows through the pad and skin, driving the medicament into thetreatment site, e.g., transdermally into an underlying site.

In another form of the invention and as noted above, the medicament canbe prepackaged in the pad of the applicator. For example, one or morerupturable capsules containing the medicament can be located in oradjacent to the porous pad, the encapsulation of the medicamentaffording long shelf life. Alternatively, the medicament may beprepackaged in or adjacent to the cells of a porous pad with removableseals for preventing exposure of the medicament to ambient conditionsthereby also affording long shelf life. Further, different applicatorscan be prepackaged with different medicaments as required for varioustreatments. With a prepackaged encapsulated, (including microencapsulation) medicament, the capsule or capsules can be ruptured bythe application of pressure to the applicator pad, thereby spreading themedicament in and among the interstices of the pad. Where seals are usedin conjunction with a medicament contained in a porous applicator pad,the seals are preferably adhesively secured to the pad and removed. Ifnecessary, the pad can then be hydrated by the user. This may beaccomplished using a separate small sterile vial of fluid by which dropsof solution are applied. The applicator is then applied by the user tothe device or to the skin or mucocutaneous membrane overlying thetreatment site or simply interposed between the device and the treatmentsite. In this manner, the device, applicator electrode and skin ormembrane are serially connected with one another for electrokineticself-administration of the medicament into the treatment site. As athird alternative, both the medicament and an electrical conductor suchas water can be encapsulated within the pad. By applying pressure, forexample, finger pressure, the medicament and hydrating capsules can beruptured, intermingling the medicament and water within or adjacent tothe porous multi-cellular applicator pad, rendering the medicamentelectrokinetically transportable under the influence of the currentflow. A fourth alternative includes pre-hydrating the pad and sealingthe pre-hydrated pad from the medicament. When the seals are broken, thehydrating material hydrates the medicament, enabling electrokineticdelivery of the medicament. Alternatively, the medicament may beencapsulated to isolate it from a pre-hydrated pad. A sixth alternativeis to encapsulate the hydration material, e.g., water or watercontaining electrolytes to enhance conductivity and medicamenttransport. A seventh alternative is to package the medicament with ahydroscopic material which will allow it to pick up water from the aironce it has been removed from its protective packaging.

It will be appreciated that the pad containing the electricallyconductive medicament or medicament hydrated to afford electricalconductivity through the pad affords a minimum barrier to the movementof the medicament molecules into the treatment site under theelectromotive force applied by the completion of the electrical current.Thus, at least a portion of the substrate or pad is preferably thin andhighly porous. The pad should be comfortable to the user and if possiblebe somewhat flexible so as to conform to the treatment site, providingfull contact coverage when in place, e.g., fabrics, absorbent gels,cotton or open celled foam. The pad should also have sufficientinterstices or open cells, i.e., porosity, to hold quantities of theelectrically conductive medicament or the medicament and hydratingmaterial to afford efficacious treatment, e.g., of herpes treatmentsites, over a period of time, for example, up to 15 minutes. For mosttreatments, the period of application is limited, for example, within arange of 1-30 minutes. The hydrating material is preferably water or avery weak trace saline solution lying within a range of 0.001-0.1%. Asan additional example of hydrating material, polypropylene glycol,polyethylene glycol or polyvinyl glycol may be used.

Further, the applicator electrode must be void of any short-circuitpaths. For example, where the applicator includes a hydrogel on anapplicator portion overlying the tactile electrode of the device, thehydrogel must be electrically insulated from the active electrode andthe conductive or hydrated medicament in the pad to ensure that thecircuit is completed through the individual's skin rather than merelyshort-circuited through the device and applicator electrode. Thedistance between the medicament containing electrically conductiveportion and the hydrogel serves as an electrical insulator, particularlywhere the substrate therebetween is non-wicking. Likewise distancebetween the active and ground electrodes of the device serve the samepurpose. Additional physical barriers may be provided, e.g., spaces,openings, valleys and ridges of non-conductive material on either orboth the device and the applicator electrode. When both are employedthey may be of a complementary nature, e.g., a valley on the device anda ridge on the applicator electrode. A portion of the barrier may alsobe hydrophilic so as to absorb any of the small amounts of hydrationmaterial which may be employed.

In a further preferred embodiment of the present invention, theapplicator may contain a magnet for activating and deactivating thepower supply in the device. Consequently, when the applicator electrodeis applied to the device or to the treatment site and the device isapplied to the applicator, the magnet cooperates with the internalelectronics of the device to activate the device. Conversely, uponremoval of the applicator from the device or the device from theapplicator, the magnet in the electrode deactivates the electricalcircuit. Other conventional switching means may also be employed, e.g.,toggle, twist or push types or the magnet may be separate from theapplicator. The applicator may also contain a code carrying system,e.g., bar code or another state of the art system, which when attachedto the hand-held device, programs the device to deliver the correctamount of medicament. This allows the hand held device to be used with arange of medicaments without having to reprogram the hand held unit.Also, indicators may be provided on the device to indicate that thedevice is actuated such that the user can be assured that the medicamentis being electromotively driven into the treatment site. Thus, forexample, one or more LEDs may be incorporated in the circuit to indicateactivation of the circuit. Other indicators or the same indicator in adifferent mode, e.g., solid vs, flashing may be employed to indicatewhen the device and applicator electrode are operating satisfactorily toelectrokinetically drive the medicament into the treatment site. Anadditional indicator can be employed to indicate low battery problems.Also, a variable timing device may be incorporated in the electricalcircuit. The circuit may be activated for a selected predeterminedlength of time and automatically deactivated after that time period haslapsed. Alternately, a timer may offer an event signal or series ofsignals to the user without necessarily reprogramming the time period.For example, if the treatment is interrupted for a brief period of time,the timer may continue timing the treatment provided the interruption isonly brief, e.g., a minute or two. If the interruption is prolonged, thetimer is automatically reset to provide a period of treatment which istherapeutically effective. Also, a non-ultrasound generated vibrationcan be added or used in lieu of the LED to indicate working status ofthe device and that the device lies in a closed current loop via theindividual's body surface.

In another form, the applicator may comprise a splint-like strip forreleasable securement to an individual's finger with self-containedelectronics, a power source and active and ground electrodes formedintegrally with the strip. The applicator strip may have a rectilinear,square, circular or shaped pad as the active electrode adjacent theindividual's fingertip. The applicator strip preferably includes a splitring for releasably securing the applicator strip to and along an insidesurface of an individual's finger. The applicator pad, which may beintegral with or form a disposable pad for the applicator strip, is incontact with the active electrode adjacent the individual's fingertipfor application to the treatment site. On the opposite side of the stripfrom the active electrode and in contact with the user's finger is aground electrode. The batteries within the applicator strip may beair-actuated by removal of a tab overlying battery terminals. After theapplicator strip is secured to the user's finger, the user then placesthe one-time use disposable applicator pad adjacent the user's fingertipand against the treatment site. This completes the circuit through thesite and the user's skin. With the applicator pad separate from theapplicator strip, the strip may be reusable with other disposable pads.Alternately, the pad may be a built-in part of the strip with or withoutpre-packaged medicament and/or hydration means, thereby enabling thewhole device disposable. The applicator may also be miniaturized to theextent that it may have a thimble-like configuration without a ring andmay be frictionally retained on the tip of the individual's finger.

In another aspect of the present invention, the applicator may comprisea completely self-contained disposable unit having its own electroniccircuitry and power source. In this aspect, the applicator may beprovided (i) without the medicament and electrically conductive material(e.g., water), (ii) with the medicament in a prepackaged form within theapplicator requiring only hydration upon use, if the medicament is notper se electrically conductive, or (iii) with both a medicament andhydration material. For example, the applicator in this form maycomprise a flexible substrate having a medicament pad on a treatmentsite side thereof, an optional hydration material layer, overlaid by afirst electrode, electronic circuitry including a power source, e.g., abattery, a second electrode and, optionally, a conductive material suchas a hydrogel. By applying the medicament-containing pad to thetreatment site and holding the applicator on the site by a finger orhand of the individual pressing on the applicator opposite the site, anelectrical circuit is completed through the second electrode, theelectronics, the medicament applicator electrode and the skin ormucocutaneous membrane between the site and the individual's finger orhand (i.e., along the finger or hand, the individual's arm, torso andsite). Consequently, the medicament is electromotively driven by theelectrical current into the site. The self-contained disposable unit maybe removed from its package by the individual upon contact of theindividual's finger with a tacky hydrogel exposed on the unit after thepackage is opened. This finger contact with slight finger pressure maycause contact between the hydration material and the medicament prior toremoval from the package. Also, the finger contact and removal from thepackage further allows highly intuitive manipulation of the unit to thetreatment site and ease of use given the lightweight and compact size ofthe unit. The unit may also be placed in a position where the fingercontact is replaced by the contact of another grounding site such aswould be the case if, by example the unit were placed in the mouthbetween the gum and inside mucosal tissue of the mouth or if the unitwere placed inside the arm and contacted the upper rib cage or if theunit were designed and formed in a fashion similar to a contact lens forocular treatments. It should be appreciated that the orientation of theactive and ground electrodes and placement of the medicament could bereversed in these or other like uses.

The battery for the circuit, for example, a zinc oxide battery, may beof the type activated by exposure to oxygen. In that battery, a taboverlies battery terminals which, when the tab is removed, exposes thecontacts to oxygen thereby activating the battery. Various other typesof miniaturized power sources may be provided, e.g., film sheet stackedbatteries. It will also be appreciated that the medicament may beapplied to the applicator pad by the user after the applicator isunpackaged and, if not per se conductive, the pad may also be hydratedby the user prior to application to the treatment site. Alternatively,the medicament may be prepackaged within the pad, for example, in one ormore rupturable capsules and if not electrically conductive per se, oneor more additional capsules containing hydrating fluid, e.g., aconductive fluid, such as water or saline may be prepackaged in theapplicator as well. By squeezing the applicator electrode to rupture thecapsule or capsules, the encapsulated medicament and, if necessary, thehydrating fluid, intermingle with one another and provide the necessaryelectrical conductivity through the applicator pad to enableelectromotive transport of the medicament through the skin. It will beappreciated that the grounding electrode lies on the opposite side ofthe applicator from the active electrode and a circuit is thereforecompleted through the individual's finger or hand holding the applicatorover the treatment site and the individual's arm and torso. To ensureelectrical contact with the individual's hand or finger and the groundelectrode, the top or outer portion of the applicator remote from themedicament pad may contain a conductive hydrogel.

In a further alternative form hereof, the applicator comprises aself-contained disposable unit likewise having its own electroniccircuitry and power source. In this form, the active electrode may forma portion of the applicator spaced from an electrically insulated groundelectrode also forming part of the applicator. The applicator isconfigured such that the first or active electrode of the applicatorlies in electrical contact with the applicator pad (electrode). Theactive applicator electrode is applied to the treatment site and theground electrode on the applicator is placed in electrical contact withthe user's skin. An electrical circuit is thereby completed through theapplicator, the applicator electrode and the treatment site with thereturn circuit through the skin, and the ground electrode of theapplicator. The spacing between the active electrode and the groundelectrode in electrical contact with the treatment site and the skin,respectively, can be quite small, i.e., on the order of one-half inch.

As mentioned previously, the medicament may be formulated as a liquid,gel, ointment, dry powder, lotion, foam, solution or cream. Where aliquid constitutes the medicament, the applicator electrode for use withthe device may include an electrically insulative housing, for example,a torus, for containing the liquid. On one side of and secured to thetorus is a microporous film overlaid by a removable barrier, e.g., foilor inert material adhered to the insulated housing to prevent transferof the liquid within the applicator electrode externally. The oppositeside of the insulative housing may likewise be confined by a barrieroverlying the housing. The insulative housing preferably has tabs forattaching the applicator electrode to the device similarly as previouslydescribed. A conductive plate may overlie the foil or the applicatorelectrode may be applied to the device directly with the activeelectrode of the device in electrical contact with the barrier. Byremoval of the adhesively secured barrier layer and application of theapplicator electrode to the site, electrokinetic transfer of themedicament can be accomplished.

In a further form, the active and ground electrodes may be spaced onefrom the other in a self-contained unit and separated by a malleable ortensioned arm. For example, the ground electrode may be adhesivelysecured to the individual at a location adjacent the medicament deliverydevice and the active electrode placed in contact with the site. Thespringbiased or malleably tensioned arm holds the active electrode withan optional gimbal component in electrical contact with the treatmentsite in a fully flush or full contact manner, avoiding only partialcontact and hence avoiding less than effective treatment. This permitshands' free electrokinetic delivery of the medicament to the treatmentsite.

In a still further form, a self-contained unit having its own electroniccircuitry and power source for hands' free application to the treatmentsite is provided. In this form, a generally U-shaped clip havingopposite ends which mount the ground and active electrodes,respectively, as well as the power source and electronic circuitry, maybe applied in a gripping or clamping manner to clip the self-containedunit adjacent the treatment site such that the active electrode engagesthe treatment site for electrokinetic delivery of the medicament.

In a still further form of the present invention, electrokineticmedicament delivery may be applied in an ocular applicator similar toand worn like a contact lens. The mechanism of the electrokineticdelivery may be multi-channel, for example, as described and illustratedin U.S. Pat. No. 5,160,316, now U.S. Pat. No. Re. 36,626, incorporatedherein by reference. Thus, a delivery device similar to a contact lensmay be employed to therapeutically treat the conjunctiva for acuteglaucoma using as an example, Xalatan or even to contour the eye bydelivering agents that retain H.sub.2 O, such as hyaluronidase orhyaluronic acid, which would swell the conjunctiva in specific sites ofthe eye. Antiviral drugs foscarnet and ganciclovir either alone or incombination may be electrokinetically delivered for treating herpeticeye infections, e.g., cytomegalovinis (CMV) and CMV retinitis.Differential levels of power and agent delivery are possible with themulti-channel delivery. In this manner, the refraction of the light canbe modified by changing or altering the shape of the eye/conjunctiva.The medicament delivery device may be worn or applied periodically forvarious time periods, for example, within a range of 1 to 60 minutes. Inthe above aspects of the present invention, the circuitry limits themaximum current available to the applicator electrode to preferably lessthan about 1 milliampere per two square centimeters of theskin-contacting surface area of the electrode. Depending upon theworking electrode's skin-contacting surface configuration, the currentlevel can vary from about 0.1 to about 1.2 milliamps. While highercurrents have been used, user discomfort can be experienced. Bufferscould be employed to overcome this milliamp range ceiling. It is alsoanother feature hereof that the electrical current can be ramped up andramped down, respectively, at the beginning and end of the treatment.See, for example, prior U.S. Pat. No. 5,160,316, now U.S. Pat. No. Re.36,626, the disclosure of which is incorporated herein by reference.Ramping contours of different configurations can be used, for example,linear, non-linear, exponential, pulsed, or otherwise shaped. Also,while direct current is preferred, alternating current can be used.

In all of the foregoing embodiments, facilitators may be employed tominimize or eliminate the barrier to the transfer of the medicamentmolecules through the skin. For example, acetic acid ordimethylsulfoxide (DMSO), alcohols, such as ethanol and isoproanol,ethyalactate, sulphoxides, fatty acids, such as oleic acid, lauric acid,capric acid and caprylic acid, sodium lauryl sulfate, acyl lactylates(except in their salt form), e.g., caprol lactyic acid and lauroyllactylic acid, esters, (1-dedecylazacycheptan-2-one) (Azone),pyrrolidones, such as dodecyl pyrrolidone, dimethyl lauramide, lineardialiphatic or aliphathic, sulfoxides, unsubstituted or mono ordi-substituted amides and di-substituted amines among others, urea,cis-urocanic acid or polyoles may be used. It may also be useful inelectrokinetic transport of some medicaments to use a second facilitatoror skin permeation enhancer which may be a monoglyceride or mixture ofmonoglyerides of fatty acids such as glycerol monolaurate (GML) orglycerol monooleate (GMO), lauramide diethanolamine (LDEA), or esters offatty acids having from 10 to 20 carbon atoms. By using thesesubstances, the skin can be disrupted, enhancing the exposure of thedermis to electrokinetic forces. Another type of facilitator is acomponent which may encase a given molecule within a lipid barrier butmakes it less polar and thereby facilitates penetration of the skin bythe medicament. An example is gylcesol or phospholipids such asphosphaticylcholine.

It will be appreciated from the foregoing that usage of the device andapplicator requires minimal instruction. Where the medicament isprepackaged with the applicator, there are no concerns regarding thedosage as a single unit dosage which is therapeutically effective overthe period of application is provided. Moreover, the device andapplicator do not require any calibration or settings as the supply ofcurrent is fixed by the device electronics. Further, there is no secondor ground electrode separate from the device whereby the device iseasily used without a separate ground electrode. The power source may belimited to providing only single use longevity. Thus, the power supplymay be replaced when a device is reused or the device itself may bediscarded. Numerous components may be constructed and linked for shortlife cycle upon use without negating a prior long shelf life. Theapplicator and even the device per se are readily disposable.

In a preferred embodiment according to the present invention, there isprovided an applicator for use in an electrokinetic device to deliversubstance to a treatment site for an individual, comprising a substrateincluding a substance-dispensing portion having a first face forelectrical contact with an electrode carried by the electrokineticdevice and a second face for electrical contact with the treatment site,a reservoir carried by the substrate for containing the substance andincluding a rupturable barrier for maintaining the substance apart fromthe substance-dispensing portion, the substance-dispensing portionproviding an electrically conductive path through the substrateincluding at least in part the first and second faces of the substratefor electrokinetically driving the substance into the treatment siteupon rupture of the barrier releasing the substance into thesubstance-dispensing portion and application of the device to the firstface and passage of an electrical current through the applicator.

In a further preferred embodiment according to the present invention,there is provided an applicator electrode for use with an electrokineticdevice to deliver a substance to a treatment site for an individual,comprising a substrate having a first surface and a second surfaceopposite the first surface, the substrate including asubstance-dispensing portion comprising a cell or a plurality of cellsforming an aperture or a plurality of apertures between the firstsurface and the second surface, a reservoir carried by the substrate forcontaining the substance and including a rupturable barrier formaintaining the substance segregated from the substance-dispensingportion, an adhesive layer covering at least a portion of the secondsurface of the substrate opposite the first surface for releasablyattaching the substrate to an electrokinetic device containing anelectrical power source for electrokinetically driving the substancethrough the first surface and into the treatment site upon rupture ofthe barrier releasing the substance into the substance-dispensingportion and application of an electrical current to effect delivery ofthe substance in the cell or plurality of cells to the treatment site.

In a still further preferred embodiment according to the presentinvention, there is provided an electrokinetic delivery device forpersonal use in self-administration of a substance to a treatment siteon an individual comprising a substrate shaped for underlying theundersurface of an individual's finger from a tip thereof to a locationpast the first finger joint, a self-contained power source within thesubstrate, a first electrode carried by the substrate and exposedadjacent the tip of the individual's finger, the first electrode beingin electrical contact with the power source, a second electrode carriedby the substrate and exposed for contact with the individual's finger,the second electrode being in electrical contact with the power sourcewhereby, upon application of the first electrode over a treatment sitewith the substance disposed between the first electrode and thetreatment site, the device applies current for electrokineticallydriving the substance into the treatment site.

In a still further preferred embodiment according to the presentinvention, there is provided a delivery device for self-administrationof a substance to a treatment site on an individual, comprising aself-contained disposable applicator including a pad for containing thesubstance, a power supply, a first electrode overlying the pad andelectrically connected to the power supply and a second electrode havinga tactile surface in electrical contact with the power supply and lyingon a side of the applicator remote from the pad, whereby, upon theindividual's hand or a portion thereof in contact with the tactilesurface of the second electrode holding the applicator pad against thetreatment site, an electrical circuit is completed between the firstelectrode through the treatment site and the second electrode via thetactile surface and the individual's hand and body forelectrokinetically driving the substance into the treatment site.

In a still further preferred embodiment according to the presentinvention, there is provided a delivery device for self-administrationof a substance to a treatment site on an individual, comprising aself-contained disposable applicator including a pad for containing thesubstance and lying on a first side of the applicator, a power supply, afirst electrode overlying the pad and electrically connected to thepower supply and a second electrode in electrical contact with the powersupply and lying on the first side of the applicator whereby, uponapplication of the applicator pad against the treatment site, anelectrical circuit is completed between the first electrode through thetreatment site and the second electrode via a portion of theindividual's body for electrokinetically driving the substance into thetreatment site.

In a still further preferred embodiment according to the presentinvention, there is provided a medicament-dispensing electrokineticdevice for delivery of a medicament to an individual's treatment site,comprising a housing having a portion thereof shaped for manualmanipulation by the individual's hand and an electrical circuitincluding a normally open switch and a first electrode formed ofelectrically conductive material and exposed for contact with themedicament, the first electrode being mounted for movement relative tothe housing between first and second positions, the first electrodeclosing the normally open switch and completing the circuit in responseto movement of the first electrode from the first position toward thesecond position, a power source forming part of the circuit andcontained within the housing, the power source having first and secondterminals, the first terminal being in electrical contact with the firstelectrode, a tactile electrode forming part of the circuit in electricalcontact with the second terminal of the power source and having asurface for contact with the individual's skin, the device beingoperable to electrokinetically drive medicament disposed between thefirst electrode and the individual's treatment site to effect deliveryof the medicament into the treatment site in response to pressing thefirst electrode toward the treatment site causing closing of the switchand completion of the electrical circuit through the closed switchbetween the first terminal through the first electrode and the treatmentsite and the second terminal via the tactile electrode and a portion ofthe individual's skin.

Referring now to the drawing figures, particularly to FIG. 1, there isillustrated a portable, self-contained, lightweight, compact, hand-heldelectrokinetic medicament delivery device, generally indicated 10,adapted for use with an applicator, described in detail below. Thedevice 10 includes an outer housing 12 containing a power source, forexample, a battery 14, and electronic circuitry including a voltagemultiplier 16 and a current driver 18. As illustrated, battery 14includes a first terminal 20 and a second terminal 22. The firstterminal 20 is coupled to the voltage multiplier 16 which steps up thevoltage supplied by the battery 14 and applies the stepped-up voltage tothe current driver 18. Current driver 18 is in contact with a first oractive electrode 24 exposed through housing 12, preferably at an endthereof. The second terminal 22 is in contact via a spring 26 and aconductor 28, with a ground or tactile electrode 30 also exposed throughhousing 12, preferably along a side wall thereof. It will be appreciatedthat housing 12 is sized and configured to be held within anindividual's hand for orientation such that the first or activeelectrode 24 can be in electrical contact with a treatment site througha conductive medicament-containing pad of an applicator, describedbelow. Thus, in a preferred embodiment, the housing 12 may be of acylindrical form, with the first or active electrode 24 at one end ofthe cylinder. It will be appreciated, however, that housing 12 canassume other shapes to facilitate the purposes of device 10, namely toprovide a portable, self-contained device having an integral powersource which, in conjunction with the applicator, may electrokineticallydrive medicament through an individual's skin or mucocutaneous membraneinto a treatment site when the applicator and device are applied to andoverlie the treatment site. For example, and referring to FIG. 2A, thehousing 12 a may have a bend intermediate its opposite ends forming ahandle 32 at one end having a tactile ground electrode 30 a exposedthrough the handle. The opposite end terminates in an active or firstelectrode 24 a similarly as in FIG. 1. Thus, the handle 32 forms a gripfor orienting and manipulating the device 10 a relative to the treatmentsite.

The circuitry limits the maximum current available to the applicator topreferably less than about 1 milliampere per two square centimeters ofthe treatment site-contacting surface area of the applicator. However,depending upon the working surface of the applicator pad in contact withthe site, the current level can vary from about 0.1 to about 1.2milliamps per two square centimeters to avoid minor discomfort anddeleterious side effects. These limitations also apply to each channelof a multi-channel device as discussed herein with reference to U.S.Pat. No. 5,160,316, now U.S. Pat. No. Re. 36,626.

The hand-held device 10 and 10 a may be modified to include apiezoelectric element 19 for imparting ultrasonic vibrational motion tothe active electrode 24 to further facilitate transdermal ortransmucocutaneous delivery of electrokinetically transportablesubstances, e.g., medicaments. The piezoelectric element 19 is locatedon the active electrode 24. Power is supplied to energize thepiezoelectric element 19 by a conductor 21 connected with the tactileelectrode 30, the piezoelectric element 19 being in electrical contactwith the active electrode 24. An optional switching element may be usedto energize the piezoelectric element or not, as desired, depending uponthe particular treatment mode. The combination of an electrokineticallydelivered substance into a tissue, together with inducing an ultrasonicvibration in the tissue, enables an opening of pores furtherfacilitating penetration of the medicament. It also facilitates removalof coloration, such as a blemish, freckle or tattoo within the skin bydelivery of a suitable bleaching agent, provided as the medicament inthe applicator, which will now be described.

Referring to FIGS. 4-6, there is illustrated an applicator, generallydesignated 40, having a treatment site-contacting side and adevice-contacting side as illustrated, respectively, in FIGS. 4 and 5.As best illustrated in FIG. 6, applicator 40 includes a substrate 42formed of a porous open cellular material. A suitable substrate materialmay comprise a fabric manufactured by Cerex of Pensacola, Fla.,identified as Type DN, Group DN07&DN15. Other suitable types ofmaterials may also be used, provided those materials, at least in theportion of the substrate through which the medicament will betransported to the treatment site, constitute a minimum barrier to thetransfer of the medicament molecules from the applicator to the site. Onthe skin or mucocutaneous side of the applicator 40 as illustrated inFIGS. 4 and 6, there is provided a pad 44 surrounded by a containmentbarrier 46. The pad may likewise comprise a porous open-cellularmaterial similar to the substrate but preferably comprises a more densematerial such as cotton for retaining the medicament. Cotton issufficiently porous and open-cellular to enable the medicament to beelectromotively driven from the cotton pad into the site. It will beappreciated that the pad 44 should be inert to the medicament, as wellas non-corrosive and stable when in contact with the medicament. Whilecotton is preferred, other suitable materials may include plastic padssuch as polyethylene, paper, porous ceramics, open-celled porouspolytetrafluoroethylene, polyurethane or other plastics, as well asopen-celled silicone rubber and vinyl.

The containment barrier 46 is formed of a non-electrically conductivematerial, which prevents the medicament from weeping or wicking ontoportions of the substrate adjacent the medicament pad. Preferably,however, barrier 46 comprises a closed-cell foam, for example, a foammanufactured by Avery Dennison of Pasadena, Calif., identified as AveryFoam Med 5637. While not shown, the foam is preferably adhesivelysecured to the substrate 42 with margins of the pad 44 frictionally oradhesively retained within the peripheral confines of the barrier 46. Aflap 48 overlies the exposed side of the pad and is preferablyadhesively secured along one side to one side of the barrier 46 suchthat the pad 44 can be exposed by lifting or removing the flap. It willalso be appreciated that the pad 44 may be incorporated or embedded inthe substrate 42. For example, the pad 44 may reside in a cutout portionin the substrate.

On the device side of the applicator and on opposite sides of the pad44, the substrate extends to form wings 52 for releasably securing theapplicator to the device. Preferably, a releasable contact adhesive 50is applied to the applicator wings 52 for releasably securing theapplicator to the device 10. For example, as illustrated in FIG. 2, theapplicator 40 illustrated in the form of a strip has a central portionof the strip, i.e., the pad 44, overlying the active electrode 24 at theend of housing 10 with the applicator wings 52 folded along oppositesides of the housing 10 and releasably secured thereto by the adhesive50. A release liner 54 is provided on the device side of the applicatoroverlying adhesive 50 and which liner 54 is removed by the user uponapplication of the applicator to the device. It will be appreciated thatother methods of releasably securing the applicator to the device may beemployed. For example, hook-and-loop type fasteners may be used with thehooks or loops on the device and the loops or hooks on the applicator.Magnets or spring clips or other mechanical-type fasteners may beemployed. The applicator as illustrated in FIGS. 4-6 is also illustratedin the form of a strip similar to a Band-Aid. It will be appreciated,however, that other configurations and shapes of the applicator may beemployed, depending upon the configuration of the device. For example,an applicator 40 a having a pad formed of similar material as pad 44 maybe employed for use with device 10 a of FIG. 2A. Applicator 40 a may beformed in a circular configuration without wings and may be adhesivelyor otherwise secured to the active electrode 24 a of housing 12 a. Forexample, the peripheral margin of the applicator 40 a may have areleasable adhesive for releasable securement to the active electrode 24a on the end of device 10 a. In this form, the applicator need not haveconductive portions overlying the ground electrode 30 a. It will also beappreciated that the applicator is formed of a flexible materialgenerally conformable to the treatment site surfaces to the extentpossible given the shape of the active electrode 24, 24 a on the device10, 10 a.

The applicator 40 is intended for a single use. That is, once themedicament has been electrokinetically driven from pad 44 into the site,the applicator may be removed from the device or the site and discarded.Where the medicament is prepackaged with the applicator, a coloringagent can be employed, such as iodine, which turns color upon contactwith the starch in the open-celled material to visibly indicate thatunit dose medicament has been used. Other types of coloring agents canbe used to indicate usage of the applicator, e.g., pH indicators, wetsaturation indicators or oxidizable pigments.

The applicator may be provided to the user without medicament within theapplicator pad 44. Thus, when using the applicator, the user may applythe medicament to the applicator pad 44 such that the medicament lieswithin the interstices of the material of the pad 44. If the appliedmedicament is not per seconductive, the pad containing the medicamentmay be hydrated by the application of water, for example, by using aneyedropper. In a preferred form, however, the medicament is supplied andprepackaged with the applicator. For example, the medicament may becontained within a rupturable polymer reservoir or capsule 56, asillustrated in FIG. 7. By encapsulating the medicament, a longshelf-life is assured. To use the applicator with the encapsulatedmedicament, the capsule 56 can be ruptured by applying pressure to thepad 44, for example, by pressing the pad between the individual'sfingers or against the active electrode when the applicator is appliedto device 10, or against a surface of packaging in which one or more ofthe applicators are provided. By rupturing the capsule, the medicamentpermeates the interstices of the pad 44. If the medicament requireshydration to afford electromotive transport into the treatment site,e.g., a lesion upon application of the electric current, the user mayhydrate the pad similarly as previously described. Alternatively, anadditional one or more capsules containing hydrating material, e.g.,water or saline, may be prepackaged with the applicator. A very weaktrace saline solution within a range of 0.001-0.1% and preferably lessthan 0.05% may be used. As illustrated in FIG. 8, the pad 44 includesone or more medicament capsules 56 and one or more hydration capsules58. By applying pressure to the two or more capsules, the capsules maybe ruptured and the medicament and hydration material intermingled withone another within the interstices of the pad 44, rendering theapplicator pad susceptible to conducting current for the electrokineticdelivery of the medicament to the lesion.

Referring back to FIGS. 4-6, a magnet 60 is preferably incorporated intothe substrate 42 on one or opposite sides of the pad 44. The electricalcircuit in the device may therefore include a magnetic field responsiveswitch for actuating and deactuating the electrical circuit. Thus, whenthe applicator is applied to the device, the circuit is activated andwhen removed, the circuit is deactivated.

Instead of or in addition to the adhesive 50, a conductive gel may beprovided within the wings 52 of the porous substrate 42. It will beappreciated that as the applicator electrode is applied to the device 10(FIG. 2), the wings 52 of the substrate overlie the tactile electrode 30of the housing 10. The conductive gel thus facilitates electricalconductivity between the individual's fingers or hand overlying the wingportions of the applicator and the tactile electrode 30 to complete thecircuit. Thus, the cells of the substrate on one or both wings 52 may beprovided with a conductive substance, e.g., a hydrogel. These wings withhydrogel are electrically insulated from the pad 44 and the medicament.Thus, electrical insulating barriers may be provided between the pad 44and the conductive wing or wings. Such barriers may comprise substantialspacing between the pad and wing with non-conductive materialtherebetween or physical barriers such as openings, ridges or valleys inthe substrate portions interconnecting the pad 44 and the one or morewings of conductive material.

To use the combination device and applicator illustrated in FIGS. 1-8,the applicator 40 is preferably applied to the device by aligning thepad 44 with the active electrode 24 on the end of housing 12. The wingsof the applicator are folded along opposite sides of the device andadhered or held to the device overlying the ground electrode 30. Withthe substrate being at least partially open celled, porous, or cutout,e.g., to contain medicament in gel, solution, cream, foam, ointment orliquid form, the individual's fingers pressing against the substrateand/or the tactile electrode 30 complete an electric circuit pathbetween the device and the individual. Where hydrogel is applied to thewings 52 of the applicator 40, the hydrogel facilitates the completionof the circuit between the individual's hand or finger and the tactileelectrode. Whether hydrogel is employed or not the individual may addwater to his/her fingers or hand, thus facilitating electricalconductivity. With the applicator 40 applied to the device, the deviceis actuated, for example, by locating the magnet 60 in a position toclose the magnetic switch within the electrical circuit. A conventionalon/off switch may be used in lieu of the magnetic switch. The activeelectrode 24 is also in electrical contact with the medicamentcontaining pad 44 by contact therewith. By manipulating the device, thepad 44 of the applicator is brought into the contact with the treatmentsite on the individual's skin. Upon contact, electrical current flowsbetween the active electrode 24 in the handpiece, through themedicament-containing pad 44 into the treatment site, through thepatient's skin, along the torso and arm for return through the finger orhand to the ground electrode 30. Consequently, the medicament iselectromotively transported through the individual's skin ormucocutaneous membrane, thus enhancing local delivery of the medicamentto the treatment site.

When using the device 10 a of FIG. 2A, the applicator 40 a may besecured to the end of housing 12 a overlying the active electrode 24 aor applied to the treatment site. The individual holding the device 10 amakes electrical contact with the ground electrode 30 a of the handle 32by grasping the handle. To ensure good electrical contact, theindividual may also add water to his/her fingers or hand. The device 10a is then manipulated to contact the active electrode 24 a through theapplicator 40 a with the treatment site thereby completing theelectrical circuit similarly as in the embodiment of FIG. 2.

The device per se may also be applied to a treatment site without amedicament, e.g., without use of the applicator 40 or 40 a. The currentdelivered to the treatment site by the device alone or with or withoutultrasonic application or enhancement has beneficial and healing effectsin the treatment of the various maladies noted previously.

Referring now to the embodiments hereof illustrated in FIGS. 9 and 10,there is illustrated a completely self-contained disposable unitcontaining electronic circuitry and a power source forelectrokinetically delivering medicament to a treatment site. Asillustrated, the self-contained unit, generally designated 70, includesa semi-flexible substrate 72, for example, formed of a plastic material,for underlying an individual's finger and shaped according to the insidesurface of an individual's finger. The substrate 72 passes along one ormore of the finger joints. The substrate 72 includes batteries 74, forexample, conventional zinc oxide batteries which may be actuated byremoval of a tab exposing battery contacts to the atmosphere.Additionally, the substrate 72 includes electronics 76 for supplying aflow of current to an active electrode 78 carried at the fingertip endof the substrate 72 and angled relative to the linear extent ofsubstrate 72. It will be appreciated that the active electrode 78 iselectrically coupled to the electronics 76 and batteries 74.Additionally, a ground electrode is electrically coupled to the otherterminal of batteries 74 and is electrically insulated from the activeelectrode 78. The ground electrode 80 may comprise a flexible material,portions of which may be in the form of a split ring 82. Thus, the fulllength of the individual's finger may be in contact with the groundelectrode, affording a good electrically conductive contact therewith.Additionally, a retainer, for example, a retaining strap 73, is providedadjacent the inner end of the substrate 72 to, in addition to the splitring 82, releasably secure the applicator electrode to the individual'sfinger. The retaining strap 73 may include semi-rigid arcuate split ringportions, a full ring integral with substrate 72 or a flexible strapwith fasteners to secure the strap ends to one another, for example,hook-and-loop type fasteners.

A similar self-contained unit 70 a is illustrated in FIG. 9A whereinlike parts are designated by like reference numerals followed by thesuffix “a.” The substrate 72 a extends along the underside of anindividual's finger but only along the finger from its tip, past thefirst joint and terminating short of the second joint. As in theembodiment of FIG. 9, substrate 72 a includes batteries 74 a,electronics 76 a, an active electrode 78 a at the fingertip, and aground electrode 80 a including split ring 82 a. Additionally, the tip71 of the substrate 72 a may curve back over the fingertip to assist insecuring the substrate to the fingertip.

The electronic circuitry for the applicator electrodes 70 and 70 a ofFIGS. 9 and 9A is illustrated in FIG. 10 and which circuitry isapplicable to all embodiments hereof. The power supply for the device 70includes an air-activated battery 74, coupled through a voltage booster75 by way of an optional low battery indicator 77. The air-activatedbatteries may be replaceable and other types of small batteries, such aslithium disks, could be used. The voltage booster 75 is connected to aservo controlled current source 79 and, optionally, to a current monitor81. The current source 79 is electrically coupled to a current limiter83 for limiting the current applied to the active electrode within thelimits previously discussed. The current limiter 83 is coupled to thetreatment electrode 78. In FIG. 10, the treatment electrode isillustrated as applied to the treatment site, e.g., a lesion, through amedicament pad 44 a. The ground electrode is also illustrated as appliedto the skin by way of an optional electrically conductive hydrogel 85.The medicament pad 44 a may be releasably or permanently secured to thedevice 70, preferably in overlying relation to the active electrode 78.Thus, the device 70 may be a one-time-use disposable or, if the pad isseparate, the device 70 may be reused with additional pads. Theoverlying pad 44 a may contain a prepackaged medicament M or any of thealternative combinations of pad, medicaments and hydration disclosed inthis application. Alternatively, the pad 44 a may be provided in aseparate package with the medicament in capsulated form as previouslydescribed. In either case, the medicament pad is applied between theactive electrode 78 and the treatment site. By removing the taboverlying the battery terminals, the power supply is activated. This maybe accomplished when opening the packaging or upon removal of the devicefrom the packaging. When the active electrode 78 is placed in contactoverlying the treatment site surface, the circuit is completed throughthe individual's body, including the finger in contact with the groundelectrode.

The applicator 70 is preferably a single-use applicator which may bediscarded after use. In an alternate form, the substrate 72 may beshaped in the form of a thimble for overlying the entirety of thefingertip of the individual. The electronics 76 and batteries 74 may beformed on the back side of the thimble opposite the side containing theactive electrode, with the ground electrode lying along the insidesurface of the thimble and electrically insulated from the activeelectrode.

Referring now to FIGS. 11A-11C, there is provided a further form of theapplicator hereof comprised of a completely self-contained disposableunit or applicator 90 integrally containing the electronic circuitry anda power source. In this form, the applicator is prepackaged for one-timeusage. For example, as illustrated in FIG. 11A, the applicator 90comprises a pad 92 for containing the medicament and, if necessary, ahydrating fluid. Overlying the pad 92 is the first active electrode 94electrically connected to electronics 96 within the applicator and whichelectronics 96 includes a power supply, for example, a battery, and thenecessary electronics for flowing a current of a magnitude previouslydiscussed through the pad to electrokinetically drive the medicamentinto the treatment site. Overlying the electronics is a ground electrode98, the surface of which remote from pad 92 comprises a tactile surface.Illustrated by the dashed lines is a packaging material 100, forexample, plastic packaging typically employed for sterilized packageswhereby the applicator 90 may be sealed within the material 100. Withthe medicament prepackaged within the pad 92, the user opens the package90. In a preferred form, the applicator 90 is connected with thepackaging 100 via a tab 102. By removing the applicator 90 from oropening the packaging material 100, the tab 102 uncovers the batteryterminals whereby the power supply is activated. In FIG. 11A, theapplicator is provided without the medicament. The user applies themedicament to the pad, hydrates the pad if necessary, and applies theapplicator to the treatment site. By applying the pad directly over thetreatment site and pressing a finger on the tactile surface of theground electrode, i.e., on the opposite side of the applicator from thepad, an electrical circuit is completed through the individual's fingerand body and through the first electrode, the pad and treatment sitewhereby the medicament within the pad is electromotively transported tothe site. To facilitate good electrical connection, the ground electrodemay have an electrical conducting fluid, e.g., hydrogel, overlying itstactile surface.

In FIG. 11B, the medicament is prepackaged in the pad 92. In FIG. 11C,both the medicament and the hydrating fluid is self-contained in thepad. For example, the medicament and the hydrating fluid can be providedin capsules rupturable by pressure applied between the opposite surfacesof the pad before, during or after removal of the applicator from thepackage 100. Further, a very weak, e.g., less than 0.05% saline solutionencapsulated and integrated between the active foil electrode 94 and themedicament with or without a porous matrix reservoir interposed betweenthe encapsulated hydration fluid and the medicament may be employed.Alternatively, adhesively attached or otherwise releasably attachedseals for sealing the medicament and the hydration fluid, if necessary,to the applicator to ensure long shelf life and integrity of the foilelectrode can be provided.

Additionally, the unit of FIGS. 11A-11C may have a tacky substance,e.g., hydrogel, not shown, overlying the ground electrode 98 within thepackage 100. Upon opening the package, the individual may contacthis/her finger on the tacky substance, facilitating removal of the unitfrom the package 100. This finger contact on the ground electrode sideof the unit also facilitates ready, direct and intuitive manipulationand application of the unit to the treatment site by the individual.

Referring now to the embodiment hereof illustrated in FIGS. 12-14, thereis illustrated a further form of applicator body or substrate 110 whichcomprises a self-contained disposable unit having integral miniaturizedelectronic circuitry and a power source. In this form, the applicatormay comprise a rectilinear or circular article having a centrallylocated pad 111 and electronic circuitry superposed over the pad. Thus,a first or active electrode 112 overlies the pad and the electronicspreviously described may overlie the first electrode. The battery 116may overlie the electronics. The first terminal of the battery isconnected through the electronics with the first electrode which, inturn, is in electrical contact with the pad 111. The second terminal ofthe battery is in contact with a ground electrode 118. The groundelectrode may be provided around the margin of the applicatorsurrounding the pad. For example, if the applicator is shaped in theform of a circle, the ground electrode may comprise an annulussurrounding and electrically insulated from the pad 111. Alternatively,if the applicator is rectilinear, the ground electrode may comprise themargin of the rectilinear applicator or lie at one end of theapplicator. In this form, the electrical circuit is completed betweenthe ground electrode and the pad. The distance between the groundelectrode and the pad may be on the order of one-half inch or more. Theground electrode need not surround the pad but may be located to oneside of the pad a suitable distance from the pad for completing thereturn circuit path through the skin between the treatment site and theground electrode.

In the applicator illustrated in FIG. 12, the pad may be providedwithout the medicament and the user may apply the medicament to the padupon removal of release liner 120. The battery may be of theair-actuated type previously discussed. Thus, the user, upon applyingthe medicament to the pad and removing the tab from the battery, mayapply the applicator over the lesion, holding both the ground electrodeabout or spaced from the treatment site and the pad in contact with thetreatment site. This completes the electrical circuit through theapplicator and the individual's skin between the ground contactingsurface and pad contacting surface. If desired, adhesive may be providedon the underside of the applicator body 110 and overlaid by the releaseliner 120 to releasably adhere the applicator including the pad 111 andground electrode 118 to the individual's skin and overlying thetreatment site. Upon completion of the treatment, the applicator may bediscarded.

Alternatively, as illustrated in FIG. 13, the applicator may beprepackaged with the medicament encapsulated within the pad. The capsuleis indicated at 122. If the medicament is itself electricallyconductive, the individual may apply pressure to the pad to rupture thecapsule, spreading the medicament into the interstices of the pad. Thiscan be accomplished while the applicator remains in its packaging. Byapplying the applicator to the treatment site similarly as previouslydescribed in connection with FIG. 12, the circuit is completed wherebythe medicament is electrokinetically driven into the site.

In FIG. 14, both the medicament and a hydrating fluid are encapsulatedin the pad. The medicament and hydration fluid capsules are indicated at122 and 124, respectively. The applicator of FIG. 14 is employedsimilarly as described with respect to FIGS. 12 and 13 after the userruptures the capsules to intermingle the electrically conductive waterand the medicament.

Referring now to FIG. 15, there is illustrated a device 130 similar tothe device of FIG. 1 and containing a power source, electronic circuitryincluding a voltage multiplier and a current driver and a tactileelectrode 132 exposed through an outer surface of the device 130.Instead of having the active or first electrode fixed to the end of thedevice 130, the active electrode 134 is mounted on the device 130 formovement in an axial direction. The movement is designed to open orclose a pressure actuated switch in the electronic circuitry to activatethe device. Thus, the active electrode 134 in an outermost positionmaintains the electronic circuitry in an off condition. Pressure appliedto the first or active electrode 134 tending to displace it toward thedevice housing closes the switch, activating the electronic circuitryfor electrokinetic delivery of the medicament.

In this form of the invention and instead of an applicator releasablysecured to an electrokinetic device, the distal face of the firstelectrode 134 may be provided with an electrical insulator ring 136defining and surrounding a reservoir 138. It will be appreciated thatthe medicament can be supplied from an ancillary tube, jar or the likein the form of a gel, cream, foam or the like and disposed by the userinto the reservoir 138 within the insulating ring 136 prior to use. Withthe reservoir filled with medicament, the device can be applied to thetreatment site similarly as the device of FIG. 2 is applied to thetreatment site. By applying a slight pressure on the device toward thetreatment site, the electrical circuit is closed. Thus, the medicamentwithin the reservoir is electrokinetically motivated into the treatmentsite, the electrical circuit being completed through the treatment site,with the medicament, the first electrode 134, the electronics, thetactile electrode 132 and the individual's hand and skin between thetactile electrode and the treatment site.

Referring now to FIGS. 16 and 17, there is illustrated a further form ofapplicator in accordance with the present invention. In this form, anapplicator, generally designated 150, may be used in conjunction withthe device illustrated in FIG. 1 and which applicator is particularlyuseful for electrokinetically delivering a liquid medicament. Theapplicator 150 may comprise an insulated annular housing 152 in the formof a torus having a central reservoir 154 for confining the liquid. Oneside of the housing 152 comprises a microporous film 156 overlaid by abarrier, e.g., foil or inert tab 158. The margin of the tab 158 hasreleasable adhesive 160 such that the barrier can be releasably attachedto one side of the housing 152. The barrier tab includes a finger tab162 for ready removal of the barrier 158 from the applicator. Theopposite end of the reservoir 154 is closed by a similar'barrier layer164 or by an optional conductive plate 166. Additionally, tabs 168 aresecured along opposite sides of the housing 152 for releasably securingthe housing 152 to the device, e.g., illustrated in FIG. 1.

As illustrated in FIG. 17, the active electrode of the device bearsagainst the optional conductive plate 166 which conducts electricitythrough the barrier layer 164 into the liquid medicament in thereservoir 154. Upon removal of the tab 158, the liquid medicament whenapplied to the treatment site can be electrokinetically driven into thetreatment site through the microporous film 156. As noted previously,the liquid within the reservoir may be per seconductive or, if notconductive, may be provided with a carrier whereby the medicament can bedriven through the porous membrane 156 into the treatment site.

Referring now to FIG. 18, there is illustrated a self-containedelectrokinetic medicament delivery device. In this form, however, theground electrode and the active electrode are separated one from theother by a malleable or tensionable arm 180. For example, the groundelectrode 182 may be provided in a housing also containing the battery184 and electronics 186. The ground electrode 182 may be surrounded byan adhesive 188 for adhering the ground electrode to a site on anindividual directly adjacent a treatment site. The active electrode 190is connected to the battery and electronics via an electrical conductorindicated by the dashed lines 192 through an arm 180. The arm may beflexed resiliently and retained in its flexed position. In utilizing thedevice of FIG. 18, the ground electrode is adhered to the individual'sskin adjacent a treatment site by the adhesive 188. The arm 180 is thenflexed resiliently to engage the active electrode 190 with the treatmentsite. By proper manipulation of the arm 180, the entire surface of theactive electrode 190 may contact the treatment site thereby avoidingless than effective treatment. A biased gimbal or pivotal connectionbetween the arm 180 and the ground electrode 182 may also be employedrather than a resilient flexible arm 180. Thus, the user may apply thedevice and have it operate hands' free, the electronics being activatedby activation of the battery as previously described.

Referring now to FIG. 19, a similar type of hands' free electrokineticmedicament delivery device is illustrated in the form of an U-shapedclip. The ground and active electrodes 192, 194 are placed at oppositedistal ends of a clip 196, preferably a spring clip. By placing theelectrodes on the inside of the clip, the clip may be applied to gentlygrip the treatment site, employing the tension of the clip to retain theclip on the treatment site whereby hands' free delivery of themedicament can be accomplished. The fully disposable U-shaped clip mayhave a built in unit dose applicator or may be reusable if fitted outfor use with disposable applicators.

Referring now to FIG. 20, there is illustrated a further form of anapplicator 200 for use with an electrokinetic delivery device 202 (FIGS.22 and 23) illustrated in a flat configuration and within packaging 204,for example, a plastic sealed package, Applicator 200 includes aflattened sleeve 206 open at its opposite ends and having an applicatorpad 208 forming part of the sleeve and projecting from one end of thesleeve and along an edge thereof. Preferably, the applicator pad 208 iscircular in form, for reasons which will become apparent and is hingedto sleeve 200 along a hinge line 209. The pad 208 is preferably a porousopen cellular material through which the medicament may be transportedto the treatment site. As in prior embodiments, the pad 208 may containthe medicament within the pad within the interstices of the opencellular material or the medicament may be encapsulated withinrupturable capsules 210, similarly as illustrated with respect to FIGS.7 and 8. A further alternative provides a pad without medicament, themedicament, and hydration material, if necessary, being applied to thepad by the user at the time the user employs the device toelectrokinetically deliver the medicament to the treatment site. The pad208 may additionally contain hydration material in a hydration capsule212 similarly as illustrated in FIG. 8 in the event the medicament isnot per se electrokinetically transportable.

As illustrated, the sleeve 206 is preferably formed of a fabric materialsimilarly as the material of substrate 42. Other suitable materials maybe employed forming all or part of the sleeve, i.e., the substrate ofany of the applicators disclosed herein may include, polyethylene,paper, cotton, ceramic, silicone rubber, polyurethane, vinyl,polytetrafluoroethlene and other plastics. A suitable barrier may bedisposed between the pad 208 and the sleeve 206 to prevent migration ofthe medicament onto the sleeve or migration of any electricallyconductive material such as hydrogel as noted below from the sleeve 206onto the pad 208. Opposite sides of the sleeve 200 may have cutouts 214which open through the end of sleeve 206 opposite the pad 208 or whichmay be completely enclosed cutouts. Particularly, the cutouts 214 lie atcircumferential positions about the sleeve 206 corresponding to theaxial and circumferential positions of the tactile electrode, forexample, electrode 30 as illustrated in FIG. 1. Additionally, a tab 216,preferably having a pressure sensitive adhesive on one face, projectsfrom the pad 208 opposite from its connection with the sleeve 206.

To use the applicator 200 in conjunction with the electrokineticdelivery device 202, the packaging 204 is removed from the applicator200. Where the medicament is encapsulated, the pad may be compressedbetween the individual's fingers to rupture the capsule 210 and hencespread the medicament into the interstices of the pad. Where themedicament is not per se capable of electrokinetic transport, thehydration capsule 212 is likewise ruptured to mix the medicament andhydration material such that upon application of electric current, themedicament may be transported to the treatment site. If, of course, themedicament has previously been applied to the pad, the user need notcompress the pad. Alternatively, if the pad contains no medicament, theuser may apply the medicament to the pad and hydration material, e.g.,water or a trace saline solution, if necessary.

As illustrated in FIG. 21, pressure applied in the direction of theillustrated arrows will form the flat applicator sleeve 206 into acylinder for reception about the end of the electrokinetic deliverydevice mounting the active electrode, for example, the deviceillustrated in FIG. 1. Upon application of sleeve 206 to the device 202,the cutouts 214 are aligned with the tactile electrode along the sidesof the device 202. Additionally, the pad 208 is folded over the activeelectrode at the end of the device 202 and the adhesive tab secures thepad 208 in contact with the active electrode. The user may then graspthe device 202 with the user's fingers pressed against the tactileelectrode of the device 202 to complete the electrical circuit, aspreviously described. It will be appreciated that the sleeve 206 mayhave, instead of cutouts 214, areas impregnated with hydrogel tofacilitate electrical contact between the individual's fingers and thetactile electrode of the electrokinetic delivery device. In anyembodiment, auxiliary hydration material, e.g., water may be employed.The sleeve may also contain magnetic switch activation material. Afterapplication of the device illustrated in FIG. 23 to the treatment site,the user removes the applicator 200 from the end of the device 202 anddiscards the applicator. The device 202 remains for subsequent use witha similar applicator or other applicators disclosed herein.

The above mechanisms may be monopolar or multi-channel (as in U.S. Pat.No. 5,160,316, now U.S. Pat. No. Re. 36,626, incorporated herein byreference), or hybrid multi-channel in nature. By hybrid multi-channelit is meant that only one current driver is employed while more than onecurrent limiter is employed to a corresponding number of two or morecurrent distributive channels. A potential problem which may possibly beencountered with hand-held, electrokinetic devices, e.g., iontophoreticdevices, is non-uniformity in contact pressure between the treatmentsurface and the active electrode surface. For a self-medicating patientusing a probe-type iontophoretic device, if the probe is accidentallyheld at an oblique angle, non-uniform contact pressure occurs. In thesmall area where the contact pressure is high, the local electricresistance is low and therefore more current flows in this small area.The resulting current concentration not only prevents a uniform deliveryof medicament but also can cause discomfort and even burns due to a highlocal current density. This detrimental occurrence can be prevented (forexample, by using a multi-channel design (segmented electrode). As thecontact pressure becomes uneven, the resistance of each channel orsegment varies. For small changes in contact pressure and resistance,the current flowing in each channel remains constant due to servocontrol. However, the bias potential or voltage of each channel willchange. For an area with higher contact pressure, and therefore lowerresistance, the bias potential will decrease. Based on this decrease inbias potential, an early warning signal for uneven probe placement canbe generated and transmitted to the patient for readjustment. If thiswarning is ignored, and the pressure concentration deteriorates further,some channel will reach its maximum bias potential limit and the currentand the concomitant medicament delivery will decrease from the pre-setlevel. For the channels where the contact pressure is high andresistance is low, the current remains constant (due to servo control ofthe current) in spite of the reduction in resistance. This is one of thebenefits of a multi-channel system where current density remainsunchanged under each segmented electrode. The non-uniform contactpressure can still cause global non-uniform medicament delivery but notburns.

An example of how the presence of non-uniform contact pressure can bedetected is illustrated in FIG. 24. For ease of explanation, assume thatthe treatment electrode is divided into four segments 25 a-d as shown inFIG. 24. Treatment currents in equal amounts, flow to electrode segments252 a-d, respectively. The current components are maintained by separateservo control loops to remain constant, irrespective of the skin andmedicament conductivity, by varying the bias potential of each electrodesegment. Under normal conditions in which the contact pressure isuniform, the bias potentials, Va, Vb, Vc and Vd for respective segmentsare substantially equal.

As shown in FIG. 24, the bias potential of each segment is connected toan analog multiplexer 254, the output of which is, in turn, connected toan analog-to-digital (A-to-D) channel of a micro-controller 256.Micro-controller 256 is an IC including a microprocessor core withdigital inputs, outputs, A-to-D converter, timer, and other functionalelements. The microprocessor can be programmed to conduct many diversetasks. It can also be programmed, for example, to periodically measureand compare the bias potential of each electrode segment. If, forexample, Va and Vb are found to be greater than Vc and Vd by apredetermined margin, the electrokinetic probe may be determined to betilted downward by the patient such that the contact pressure is higherunder segments C and D, and lower under segments A and B. Themicro-controller can cause an alarm 258 to output an aural and/or visualalarm when the non-uniformity in contact pressure (as determined fromthe bias potentials) exceeds some predetermined value. Instead of usinga micro-controller, the non-uniform pressure detection can also beaccomplished by using discrete analog circuitry with operationalamplifiers, comparators etc.

Fungal infestations of skin and its appendages are also quite common andmultiple therapies are available. The infections afflict age groups fromchildhood to late adulthood and the aged and immune suppressedpopulation. The infections may include, for example, diaper rash,athlete's foot or jock itch and, in children, ringworm and otherdermatophytosis. The current treatment of such infections involveanti-fungal agents applied topically. In healthy patients, the topicaltreatment works, although sometimes frustrating in its response time andchances for recurrence.

Fungal infections of the nail bed are more refractory to standardmanagement. These frequently distort the nails both on the feet and handand commonly occur in people working in gardens. These infections createdeformity of the nails and patients frequently ask for treatment.Unfortunately, the current treatment involves systemic drugs that havesignificant liver toxicity as well as side effects. Many patients failto undergo the typical eight weeks of treatment required to control suchinfections.

As described herein, the present invention offers a more rapidresolution of topical infections and more effective non-systemictreatment of the more refractory nail infections. As in the priorembodiments, the treatment method and apparatus for fungal infestationemploys an electrokinetic, e.g., iontophoretic transport mechanismincluding electronics to drive the medicament into the infected(treatment) site to ultimately prevent the fungus from replicating.There are numerous medicaments available on the market for this purpose.In addition, there are several non-pharmaceutical level agents that mayhave a significant benefit to the treatment of fungal infections.

Referring to FIG. 25, there is illustrated an applicator 270 for thetreatment of athlete's foot, e.g., where fungal infestation occursbetween the toes. The applicator 270 is in the form of a flexibleelastic sock electrode with an electronics package 271 containing abattery 272, electronics 274, ground electrode 276 and active electrodes278 in registration with fungal infested areas between the individual'stoes. The package 271 is strapped about the individual's ankle by astrap 273. Discrete medicament-carrying pads 280 are shaped to extendbetween the toes along the interior potion of the toe region of thesock. Individual branch wires 284 overlying the pads 280 and with anelectrically insulative covering, not shown, are coupled to theelectronics package by conductive wire leads 285 disposed in aninsulative protective ribbon 286. By wearing the sock, e.g., one to twohours, and completing the circuit between each active electrode 284 andthe ground electrode 276 through the individual's ankle, a singletreatment is sufficient to drive the anti-fungal medication carried bythe pads 280 into the infected area between the toes to completelyresolve the fungal infestation. It will be appreciated that the pads mayform an integral part of the elastic sock 270 preferably along theinside portion of the toe region. The medicament is preferablypre-supplied within the pads, e.g., encapsulated and with or withouthydration material as in prior embodiments hereof. The sock 270 may alsobe disposable with the electronics package 271 or the electronic packagemay be disconnected and reconnected to one or more additional socks asneeded for applying additional medicament at the appropriate treatmentintervals.

A similar arrangement is illustrated in FIG. 26 for electrokineticapplication of medicaments to toenail fungal beds. In this form, theelastic sock 290 includes active electrode portions 292 overlying a pad293 containing the anti-fungal agent in the region of the sock overlyingthe individual toenails. Each active electrode portion 292 may compriseshort individual lead wires 294 coupled via individual leads 296 to anelectronics package 298 similar to the package described and illustratedwith respect to FIG. 25. Thus, electrokinetic delivery of the medicamentto the nail beds of the toes is provided upon completion of the circuitthrough the active electrodes 294 and ground electrode in theelectronics package 298 through the ankle of the individual. Thistreatment requires prolonged and overnight wear of the sock electrodeand may involve a plurality of treatments, for example, three treatmentswith a spacing of about two or three days.

Referring now to FIGS. 27 and 28, there is illustrated an applicator forthe treatment of fingernail fungal beds. In this form, an applicatorbody 300 may be generally hemispherical in shape and is preferablyformed of a resiliently elastic material. In the arcuate surface of thehemispherically-shaped body 300, there is provided one or morefingerholes 302 into which the individual's fingernails may be received,e.g., up to about the first finger joint. Thus, five fingerholes 302 canbe provided at various positions about the body 300 consistent with theanatomical orientation of an individual's bent fingers when his/her handrests on the arcuate upper surface of the body 300 enabling thefingertips to be received in the openings 302.

As best illustrated in FIG. 28, the body 300 includes an activeelectrode 304 in each of the openings 302 at a location in registrationwith, i.e., opposite, the fingernail of the individual's finger whenreceived in the hole. A medicament-containing porous pad, for example,in the form of a thimble 306, preferably pre-supplied with medicament orhaving encapsulated medicament along a forward edge thereof is provided.Alternatively, the individual user may apply the medicament to thethimble pad portion upon use. The thimble 306 may also contain aresilient elastic material 308, for example, sponge material, such thatupon placing the thimble about the individual's fingertip and thefingertip including thimble 306 in the hole 302, the sponge material 308biases the individual's nail forwardly into contact with the forwardmostpad portion of the thimble to make electrical contact with the activeelectrode 304. As in the prior embodiments, hydrating material may alsobe supplied integrally with the thimble, for example, in the form ofencapsulated hydration material or the individual may hydrate themedicament in the thimble pad portion upon use.

As illustrated in FIG. 28, the ground electrode 310 is provided along anarcuate surface of the body 300 such that when the individual layshis/her hand over the arcuate portion of the body 300, the palm of thehand rests against ground electrode 310 with the finger or fingers inthe holes 302 bearing against the pad 306 and active electrodes 304. Itwill be appreciated that each hole 302 has an active electrode 304associated with that hole. The active and ground electrodes are coupledto the electronics 312 which, in turn, is coupled to a power source 314integral with body 300. It will be appreciated that the body 300 mayhave other shapes, for example, an elastic spherical shape, such thatthe individual can carry the electrokinetic delivery device in his/herhand for the duration of the treatment period. Alternatively, asillustrated, the body 300 may have a flat undersurface enabling theindividual to rest his/her hand on the upper arcuate surface of the body300 with body 300 supported, for example, on a desk or table.

As will be appreciated from the above description, a variety of activeelectrodes can be designed for size and contour for application tovarious parts of the human body. For example, electrodes can be woveninto undergarments to alleviate refractory infestation in the inguinalarea, commonly described as jock itch. Moreover, applicators such as thesock electrodes described, are disposable items with prescribedmedication pre-supplied for specific application.

Referring now to the embodiment hereof illustrated in FIGS. 29-31,various medicaments may be electrokinetically applied in an ocularapplication similar to and worn like a contact lens. For example, asillustrated in FIG. 29, there is provided an electronics package 320comprised of a battery 322, electronics 324 and a ground electrode 326carried by a strap 328 designed to envelope the individual's headreleasably securing the electronics package 320 on the forehead with theground electrode engaging the individual's forehead. Contrary to thepreceding embodiment, the mechanism of the electrokinetic delivery maybe a multi-channel electrode as described in U.S. Pat. No. 5,160,316,now U.S. Pat. No. Re. 36,626, incorporated herein by reference, Whiledelivery of medicament is illustrated as being applied to both eyessimultaneously, it will be appreciated that the electrokinetic deliverysystem hereof can be applied to only one eye.

As illustrated, the electronics of the package 320 are coupled to anapplicator electrode 330 for each eye via a ribbon cable connector 332.The applicator electrodes 330 are each in the form of a concave-convexmatrix formed of electrodispersive material sufficiently flexible to fitand overlie the various contours of individual eyes. Each matrix issimilar to a contact lens. Applicator electrode 330 includes a combinedhandle and connector 334 which projects from the convex side of theapplicator electrode 330, facilitating a finger grip for the contactelectrode 330 and an electrical connection for the ribbon connector 332.The individual lead wires in the ribbon connector 332 are continuedthrough the combined handle and connector 334 into the electrode 330. Asillustrated in FIG. 31, these individual conductors or lead wires 336extend from the combined handle and connector 334, preferably insemi-circular patterns along opposite halves of the contact electrode330. Each of the conductors 336 has a plurality of short lead wires orsupplemental conductors 338 at spaced positions along each connector 336to provide increased contact area, i.e., to further distribute theelectrical current flow along the surface of the eye. Each of the leadwires or connectors 336 has a discrete pad 339 associated with it forcarrying the medicament and which medicament is electrokineticallydriven into the eye upon completion of the electrical circuit betweenthe applicator electrode 330, the eye, the individual's skin between theactive and ground electrodes, and the ground electrode 326.

As noted in the aforementioned patent, the lead wires 336 in eachcontact electrode 330 may be electrically driven simultaneously or insequential multiplex fashion. With the current in each connector 336being limited, for example, within the range previously discussed,current tunneling or current flow along the path of least resistance issubstantially eliminated. For delivering medicaments, the ocularelectrokinetic delivery system described herein is preferably worn by anindividual over a period of time, for example, up to an hour, with themulti-channel driver electrokinetically delivering the medicament intothe cornea. Further, the contour of the eye can be reshaped bydelivering agents that retain water which would swell the conjunctiva inspecific sites of the eye. By applying differential levels of power andagent delivery through use of a multi-channel system, the refraction oflight can be modified by altering the shape of the eye.

While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiment,it is to be understood that the invention is not to be limited to thedisclosed embodiment, but on the contrary, is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

B. Method and System for Electrokinetic Delivery of a Substance

The present invention is described in the context of exemplaryembodiments. However, the scope of the invention is not limited to theparticular examples and embodiments described in this specification.Rather the specification merely reflects certain embodiments and servesto illustrate the principles and characteristics of the presentinvention. Those skilled in the art will recognize that variousmodifications and refinements may be made without departing'from thespirit and scope of the invention. A method and system for the safeapplication of an electrokinetic delivery system, such as iontopheresis,is described with reference to FIGS. 32 through 35. The method andsystem are based on the use of a high frequency rectified current inconjunction with three electrodes, referred to herein as a treatmentelectrode, a counter electrode and an auxiliary electrode. For purposesof illustration, transdermal delivery of morphine is used as an example.It will of course be appreciated that the method and system describedherein are usable in connection with substances generally includingnatural or homeopathic products that may be outside the definition ofmedicaments as well as medicaments (e.g., lidocaine for transdermalanesthetization, anti-viral agents for herpes infections, andanti-fungal medicine for athlete's foot) and in connection with barriersother than skin (e.g., cell membranes, mucosal membranes, etc.). Bymedicament is meant any chemical or biologic that may be used on oradministered to humans or animals as an aid in the diagnosis, treatmentsor prevention of disease or other abnormal or cosmetic condition or forthe relief of pain or to control or improve any physiologic orpathologic condition.

As described above, iontophoresis involves the use a current to delivera substance to tissue. In conventional systems, there is a potentialhazard associated with ventricular fibrillation and cardiac arrest ifthe current generated during iontophoresis accidentally passes throughthe patient's heart. The standard current threshold for ventricularfibrillation risk increases with frequency. FIG. 32 is a graph of riskcurrent (RMS) in microamperes versus frequency showing the risk currentlimits based on fibrillatory thresholds. For direct current (DC), thelimit is 10 microamperes. For frequencies from 1 kilohertz to 100kilohertz, the risk current limit varies from 10 microamperes to 1milliampere. For frequencies above 100 kilohertz, but below 1 megahertz,the risk current limit remains at 1 milliampere. See, for example, AAMI(Association for the Advancement of Medical Instrumentation) Standard,“Safe Current Limits Standard.”

FIG. 33 shows an iontophoretic delivery system 300 in accordance with anembodiment of the present invention. System 300 includes a treatmentelectrode 302, a counter electrode 304 and an auxiliary electrode 306connected to a 100 kilohertz alternating current source 308. Electrodes302, 304 and 306 are in electrical contact with the patient's skin viaconductive layers 312, 314 and 316, respectively. Such layers may, forexample, be part of a medicament-carrying substrate or pad. Themedicament-carrying substrates or pads are generally disposable andnon-reusable and may be releasably adherable to the patient's skinand/or to electrodes 302, 304 and 306. Conductive layer 312 is shown inFIG. 33 as comprising a medicament-soaked sponge or other porous opencellular material, such as cotton, and conductive layers 314 and 316 areshown in FIG. 33 as each comprising a saline-soaked sponge or other suchmaterial.

For example, conductive layer 312 may be of a mesh-like constructionhaving vertical cells dimensioned to accommodate a viscous fluid withinthe confines of the cellular structures. The viscous fluid containedwithin the plurality of cells includes a medicament that is in a formsuitable for transport under the influence of an electric current.Conductive layers 314 and 316 may be mesh-like tactile conductiveportions that contain an electrically conductive gel or fluidtherewithin. Each of the conductive layers has a lower skin-facingsurface and an upper electrode-facing surface. The cells form aperturesbetween the lower skin-facing surface and the upper electrode-facingsurface. The device-facing surfaces of the electrodes may furtherinclude an adhesive layer applied thereto for suitably releasablyadhering the electrodes to the iontophoresis device.

Auxiliary electrode 306 is located lateral to, behind or near treatmentelectrode 302. Auxiliary electrode 306 and treatment electrode 302 canbe in close proximity to each other and the area of auxiliary electrode306 can be very small compared to the area of treatment electrode 302.These features permit design of a compact hand-held unit in spite of theaddition of an auxiliary electrode. In one particular implementation,the total area can be reduced to a minimum by placing auxiliaryelectrode 306, in the form of a metal mesh, in front of treatmentelectrode 302. The open mesh allows free passage of medicament and ionsto and from treatment electrode 302. Of course, auxiliary electrode 306may be positioned elsewhere and the present invention is not limited inthis respect.

Treatment electrode 302 is connected to AC source 308 via a current pathincluding a first rectifying element 320 for passing current flowingfrom AC source 308 to skin (and tissue) 310 and blocking current flowingfrom skin (and tissue) 310 to AC source 308. In the illustrative FIG. 33embodiment, first rectifying element 320 is a diode having its anodeconnected to AC source 308 and its cathode connected to treatmentelectrode 302. Auxiliary electrode 306 is connected to AC source 308 viaa current path including a second rectifying element 322 for passingcurrent flowing from skin (and tissue) 310 to AC source 308 and blockingcurrent flowing from AC source 308 to skin (and tissue) 310. In theillustrative FIG. 33 embodiment, second rectifying element 322 is adiode having its anode connected to auxiliary electrode 306 and itscathode connected to AC source 308. Counter electrode 304 is connectedto AC source 308 via a bi-directional current path over which currentcan flow from AC source 308 to skin (and tissue) 310 and from skin (andtissue) 310 to AC source 308.

In use, treatment electrode 302, counter electrode 304, auxiliaryelectrode 306 are placed in electrical contact with skin 310 viaconductive layers 312, 314 and 316, respectively. Conductive layers 312,314 and 316 may be releasably attached to the electrodes and/or to skin310 using, for example, a releasable adhesive. Iontophoretic system 300is then turned on using, for example, a switch (not shown in FIG. 33).During the positive cycle portions of AC source 308, a component currentI.sup.+ flows from treatment electrode 302 to the patient's skin andtissue and from the patient's skin and tissue to counter electrode 304.In this way, for example, morphine HCL ions (MH+) are delivered to thetissue covered by the patient's skin. During the negative cycle portionsof AC source 308, a component current I.sup.+ flows from counterelectrode 304 to the patient's skin and tissue and from the patient'sskin and tissue to auxiliary electrode 306.

FIG. 34 is a block diagram showing electronic circuit design elementsused in an illustrative implementation of a high frequencyunidirectional iontophoretic medicator in accordance with an embodimentof the present invention. In this example, power source 402 is a batterycomprising one or more AAA-sized primary cells connected either inseries or in parallel. Counter electrode 304 is connected to an outputof current driver 408 (see FIGS. 34 and 35). An optional conductivelayer 314 (such as a conductive gel or a saline-soaked sponge) is usedto facilitate current flow to and from the patient's skin. An internalmechanical or electronic switch 404, activated externally by a magnet ormagnetic material 520 (see FIG. 35), controls the on and off status ofthe device. A voltage booster circuit 406 converts the low batteryvoltage (e.g., 1.5 to 3 VDC) to a high voltage around 30 VDC. The highvoltage or high potential is preferred to allow a current driver 408 toovercome any tissue resistance. An oscillator circuit 410 generates asquare-wave or sinusoidal AC signal with the selected operatingfrequency (e.g., 100 kilohertz). A servo-controlled amplifier 412, insynchronization with the oscillator signal, controls the currentmagnitude based on current feedback signals from a current sensor 414. Acurrent driver stage 408 controls the bias voltage and maintains thedesired current to treatment electrode 302. A redundant current limiter416 is used to provide a safe upper limit for the treatment current. Alow battery voltage indicator 418 (e.g., an LED) signals when thebattery capacity is low.

FIG. 35 illustrates a hand-held device 500 into which the variouscircuit elements of FIG. 34 may be incorporated. Of course, it will beapparent that the circuit elements of FIG. 34 may be incorporated in awide variety of devices and the device of FIG. 35 is provided by way ofillustration, not limitation. The hand-held device shown in FIG. 35 isconfigured along the lines of the hand-held devices shown in U.S. Pat.Nos. 5,676,648, 5,879,323 and 5,908,401, the contents of each of whichare incorporated herein by reference. For ease of illustration, not allof the elements shown in FIG. 34 are shown in FIG. 35, Housing 506 ofthe handheld device is preferably formed of plastic and is shaped tocomfortably fit within a user's hand. Medicament-soaked sponge 312 is inelectrical contact with treatment electrode 306. A mesh or griddedauxiliary electrode 306 is, as an example, interposed between treatmentelectrode 306 and the patient. Negative battery terminal 502 isconnected via an electrical connection 508 to an electronic package 516,and an output of a current drive circuit within electronic package 516connects to counter electrode 304 provided as a metal band 510circumferentially (either continuously or discontinuously) formed aroundhousing 506. For the self-administration of medicament, a user touchescounter electrode 304 with his/her skin (e.g., fingers). Electricalconnection 508 includes a spring portion 512 for holding power source(battery) 402 in place. Positive battery terminal 504 is connected toswitch 404 (e.g, a mechanical reed switch or an electronic switchactivated by an external magnet denoted at 520). Element 516 in FIG. 35designates an electronic package at least containing oscillator 410,amplifier 412, current driver 408, redundant safety current limiter 416,current sensor 414 and rectifying elements 320 and 322. Some or all ofthe components within housing 506 may be contained in epoxy 518.

As described above, in cases in which iontophoresis treatments areadministered by a patient without the supervision of medicalprofessionals (e.g., at home), current may accidentally pass through thepatient's heart. With conventional equipment, the portion of the currentdirectly traversing the patient's heart could reach a level resulting inventricular fibrillation. In accordance with the above-describedembodiment of the present invention, the frequency of the electricaldriving circuit is increased from 0 (DC) to 100 kilohertz. As can beseen with reference to FIG. 32, in this case, the current can be safelyincreased up to 1 milliampere (RMS). This results in effective deliveryof the medicament to the patient. Thus, the use of rectifiedhigh-frequency iontopheresis as described above satisfies theestablished risk-current limit requirements and eliminates the hazard ofventricular fibrillation. In addition, the goal of unidirectionaliontophoresis like that of the DC approach can be obtained. Therefore,although the AC current is rectified at the treatment site to obtainDC-like, unidirectional iontophoresis, any current passing through theheart remains strictly bi-directional and alternating with a frequencyhigh enough to meet the risk current requirement.

In rare cases in which AC iontopheresis is applicable, the hazardassociated with ventricular fibrillation can also be eliminated by usinga high frequency current source around 100 kilohertz. In this specialcase, rectifying elements and auxiliary electrode 102 are not requiredbecause AC iontophoresis is desired. The same circuit design used forunidirectional AC electrophoresis (FIG. 34) is directly applicable.

While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiment,it is to be understood that the invention is not to be limited to thedisclosed embodiment, but on the contrary, is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

C. Electrokinetic Delivery System for Self-Administration of Medicamentsand Methods Therefor

Referring now to the drawing figures, particularly to FIG. 36, there isillustrated a portable, self-contained, lightweight, compact,finger-mounted, electrokinetic medicament-delivery device or medicator,generally indicated 10 applied to a treatment site on an individual. Thedevice 10 includes a housing 12 mountable to an individual's finger, forexample, by straps 14, with a tip 16 of the device 10 mounting an activeelectrode for driving, i.e., electrokinetically transporting, medicamentinterposed between the active electrode and the individual's treatmentsite into the treatment site upon completion of an electrical circuitthrough the device, the active electrode, the medicament or hydrationmaterial carrying the medicament, the individual's body and a counterelectrode, i.e., tactile electrode carried by the device. Asillustrated, the tip 16 of device 10 housing the active electrode liesadjacent to and underlies the fingerprint portion of the tip of a digit,preferably an index finger, of an individual's hand, enabling the deviceto be easily manipulated by the individual's arm, hand and finger suchthat the active electrode at the tip of device 10 may be disposed inoverlaying relation to a treatment site with the medicament ormedicament-carrying substrate interposed therebetween.

Referring to FIG. 37, the device 10 is preferably provided in two parts:a first part or proximal portion 20 and a second part or distal portion22. It will be appreciated that the device 10 is substantially rigid inconstruction, is preferably formed of a plastic material, although othermaterials may be utilized, and, while a two-part device is preferred, aunitary device or a device formed of more than two parts may beprovided. Additionally, while the two parts, when assembled, provide asubstantially rigid device, the parts may be interconnected by flexibleportions, enabling the device to flex with the flexing of theindividual's finger. As explained below, the proximal and distalportions 20 and 22 are connected together to form part of an electricalcircuit between an active electrode carried by the distal portion 22,and a power source, tactile electrode and other electronics carried bythe proximal portion 20.

The proximal portion 20 includes a compartment 24 for receiving a powersource 25, e.g., a 1.5 volt silver oxide battery, as well as anelectronics pod 26 for carrying the electronics described below. Thecompartment 24 may include a removable cover 28 affording access withinthe compartment. Preferably, however, the compartment is sealed.

Proximal portion 20 is elongated and shaped and configured to overlie aportion of an individual's finger, preferably an index finger, alongopposite sides of the first finger joint, as best illustrated in FIG.36. That is, forward and rear portions 30 and 32, respectively, of theproximal portion 20 are slightly angled relative to one another tostraddle the first finger joint (the joint between the first and secondphalanges of a digit) at the apex of the forward and rear portions 30and 32. Also, the proximal portion 20 has a concave surface along itsunderside, as best illustrated in FIG. 38, to comfortably overlie andsubstantially conform to the outer convex portions of the individual'sfinger on opposite sides of the first finger joint. Adjacent one sideand along a margin of proximal portion 20, there are provided a pair oflaterally projecting loops 34. Along the opposite margin of proximalportion 20, there are provided a pair of tabs 36. Straps 14 (FIG. 36)are secured in the loops 34. The opposite ends of the straps have one ofhook-and-loop fasteners, while the outer surfaces of the tabs 36 carrythe other of hook-and-loop fasteners (Velcro®), thereby enabling thedevice 10 to be releasably secured to an individual's finger. Othermeans for releasably securing the proximal portion 20 to theindividual's finger may be provided. For example, one or more rings orsleeves may be mounted directly to the proximal portion 30 for receivingthe individual's finger. Arcuate sections may project from oppositesides of the proximal portion 30 to form one or more resilient splitrings for engaging along opposite sides of the individual's finger,their distal ends being spaced from one another along the inside surfaceof the individual's finger. Elastic straps, buckle-type fasteners, andsnap fasteners on elastic or flexible straps may also be utilized. Othertypes of releasable securements will be apparent to those of skill inthis art.

The distal portion 22 of device 10 includes a generally frustoconicalsection 40 (FIG. 37) sized and configured to receive the tip of anindividuals finger, the smaller diameter end of section 40 forming anopening 41 and comprising the outer end of the device. The distalportion 22 may include a closed annular ring as illustrated or a splitring. However, an open-ended frustoconical section having afrustoconical interior surface is preferred because it affords greatercontrol and stability to the active electrode when the medicator ismanipulated by the individual to engage the treatment site. Also, thesmaller end 41 of the frustoconical section 40 is open to enable theindividual's fingertip, including the tip of the individual's nail, toproject from the device. It will be appreciated, however, that distalportion 22 may be extended and closed if desired. As illustrated in FIG.37, a pair of electrical contacts 42 project from the distal portion 22for engagement in mating electrical sockets 44 formed on the distal endof the proximal portion 20. Thus, when the distal and proximal portionsare secured to one another, the power source and electronics of theproximal portion are electrically connected with the active electrodeand a counter electrode 60 carried by the distal portion 22. Note alsothat the juncture of the proximal and distal portions 20 and 22,respectively, lies adjacent the second joint between the second andthird phalanges of the digit leaving the third phalange of the digit forreception within the frustoconical interior of the distal portion 22.

Referring to FIGS. 38-41, preferably a circular annular housing 50 isprovided along the underside of the distal portion 22 and forms part ofan applicator head 51 of the distal portion 22. Housing 50 includes anactive electrode 54, preferably in the form of a metal disk, mounted atthe base of a circular recess 52 (FIG. 41) in housing 50. The activeelectrode 54 is in electrical contact with the power supply andelectronics in the proximal portion 20 when the portions 20 and 22 areconnected one with the other. Particularly, a spring 55 in housing 50interconnects the active electrode 54 and electrical connections 57within the distal portion 22 in electrical contact with contacts 42(FIG. 37). As illustrated in FIG. 41, a substrate 56 is disposed in therecess 52, and is preferably formed of a porous, open-cellular, inertmaterial. The substrate material may comprise a non-woven fabricmanufactured by Cerex of Pensacola, Fla., identified as Type DN, GroupDN07 & DN15. Other suitable types of materials may also be used,provided those materials, at least in the portion of the substratethrough which the medicament will be transported to the treatment site,constitute a minimum barrier to the electrokinetic transfer ofmedicament molecules from the substrate to the treatment site. Thesubstrate 56 preferably conforms to the shape of recess 52, e.g.,substantially circular, and may be frictionally maintained within thehousing and bearing against active electrode 54. Alternatively, othermeans may be provided to secure the medicament containing substrate tothe housing 50. For example, the recess 52 may include an inwardlydirected flange or lip for retaining a substrate within the recess. Apreferred embodiment for releasably securing the substrate in the recess52 in electrical contact with the active electrode 54 is described belowwith reference to FIG. 42.

It will be appreciated that the substrate 56 may be provided to the userwith or without medicament. Thus, when using the finger splint medicatorhereof, the user may apply the medicament to the substrate such that themedicament lies within or wicks into the interstices of the material ofthe substrate. If the applied medicament is not per seconductive, thesubstrate may also be hydrated by the application of water, for example,by using an eyedropper. In the preferred form, however, a unit dose ofthe medicament is supplied with and prepackaged in the substrate 56. Themedicament permeates the interstices of the porous substrate 56 and thesubstrate with the medicament is disposed within the recess 52 of thedistal portion 22 of the device 10 and factory-sealed. For example, asillustrated in FIG. 42, a retainer ring 59 may overlie the substrate 56and a release film, e.g., a foil lid 63 having a finger pull or tab 65,may overlie the substrate 56 exposed through the end of the retainerring 59. By removing the lid 63 prior to use, the medicament permeatedin the substrate is exposed for electrokinetic transport into thetreatment site.

Alternatively, a unit dose of the medicament may be pre-filled andcontained within a rupturable polymer reservoir or capsule within thesubstrate 56 as in U.S. Pat. No. 5,676,648, issued Oct. 14, 1997, thedisclosure of which is incorporated herein by reference. Byencapsulating the medicament in a rupturable reservoir or sealing amedicament-permeated substrate, whether within device 10 or separatetherefrom, a long shelf-life is assured for medicaments. Anon-pre-filled substrate may also be provided the user with themedicament provided separately. In that instance, the user may apply thesubstrate to the distal portion 22 (if not already contained withinhousing 50) and either apply the medicament to the substrate beforeapplication of the device to the treatment site or interpose themedicament between a suitably hydrated substrate (if auxiliary hydrationis required) and the treatment site whereby electrokinetic transport ofthe medicament into the treatment site can be accomplished. To use thesubstrate with the encapsulated medicament, the capsule(s) can beopened, for example by peel-away means, such as peeling away a releasefilm, or ruptured by applying pressure to the substrate, for example, bypressing the substrate toward the active electrode 54 after thesubstrate has been located within the recess 52 of the applicator headeither upon manufacture or by the user. By rupturing the capsules, themedicament permeates the interstices of the substrate. If the medicamentrequires hydration to afford electromotive transport into the treatmentsite upon application of the electric current, the user may hydrate thepad similarly as previously described. Alternatively, an additional oneor more capsules containing hydrating or conductive material, e.g.,water or saline, and/or another formulation excipient(s) such as sodiumlauryl sulfate with or without cetostearyl alcohol may be prepackagedwithin the medicament and or substrate.

The substrate 56 is intended for single use only. That is, once themedicament has been electrokinetically driven from the substrate intothe treatment site, the distal portion 22 is disconnected from theproximal portion 20 and discarded without the consumer/patient touchingthe medicament or substrate. It is important to prevent reuse of thedistal portion and its used substrate and to render it disposable. Forexample, active disease particles or other biologic material on thesubstrate could cause cross-contamination if reused. Insufficientdosage, dehydration or degradation of the medicament could occur ifreused. Physical separation of the substrate from the active electrodecould occur, rendering dosage or even operability problematical uponreuse. Alternatively, the substrate 56 may be removed from theapplicator head 51 and discarded and a new substrate applied to theapplicator head. Where the medicament is prepackaged with the substrateeither by permeation within the substrate with a release film or foilseal or within a releasable or rupturable capsule within or near thesubstrate, a coloring agent can be employed, such as iodine, which turnscolor upon contact with starch in the open-cell material to visiblyindicate that a unit dose of medicament has been used. Other types ofcoloring agents can be used to indicate usage of the applicator, e.g.,pH indicators, wet saturation indicators or oxidizable pigments.

Referring to FIG. 41, it will be appreciated that the device 10 isgenerally elongated and extends generally parallel to the individual'sfinger 71 when in an extended position as illustrated. The housing 50extends at an angle relative to the direction of elongation representedby a centerline 73 in FIG. 41 of the device which generally parallelscentral portions of the individual's finger when extended. Thus, theouter planar face of the active electrode 54 extends at the same angleas the housing relative to the elongated device and faces outwardly andaway from the device and the individual's finger. The angle at anintersection between the direction of elongation (centerline 73) and aline through the planar surface of the active electrode 54 is an obtuseangle of approximately 160.degree, but may lie within a range of about100.degree.-185.degree. The angular direction of the active electroderelative to the device 10 facilitates application of the device totreatment sites variously located about an individual's body.

Reverting to FIG. 37 and in a preferred embodiment, the counterelectrode 60 is located in the distal portion 22 on the bottom of theinterior frustoconical surface. Counter electrode 60 may be covered witha conductive material, e.g., water or hydrogel, to facilitate electricalcontact with the underside of the individual's fingertip. The counterelectrode 60 is electrically insulated from the active electrode. Thecounter electrode 60 is electrically coupled to the terminal of thebattery opposite the battery terminal to which the active electrode 54is coupled when the distal and proximal portions are electricallyinterconnected with one another. It will be appreciated that by locatingthe counter electrode 60 along the inside surface of the distal portion,the act of inserting the individual's fingertip into the opening in thedistal portion ensures good electrical contact between the counterelectrode and the individuals finger. Alternatively, the counterelectrode may be exposed along the underside of the proximal portion 20for engagement with the individual's finger upon the individual donningthe finger splint medicator. In a further alternative, the counterelectrode may be located along the underside of both the proximal anddistal portions 20 and 22, respectively. Thus, a full-length portion ofthe individual's finger on opposite sides of the first finger joint andincluding the fingertip may be in contact with the counter electrode, ineither case, affording a good electroconductive contact therewith.

Referring to FIG. 43, there is illustrated a portion of an applicatorhead 51 a in conjunction with a substrate 56 a separate and apart fromthe device per se. The applicator head 51 a is similar to the applicatorhead 51, except that the active electrode 54 a forms a circularprojection from the applicator head 51 a. Also illustrated in FIG. 43 isa substrate 56 a which has been removed from a package, not shown, andwhich substrate contains the medicament. With the substrate 56 acontaining the medicament interposed between the active electrode 54 aand the treatment site T.S., it will be appreciated that upon completingthe electrical circuit by coupling the distal and proximal portions toone another, the medicament in the substrate may be electrokineticallymotivated into the treatment site. As a further alternative, themedicament can be applied by a user directly to the treatment site or toa non-prefilled substrate, together with any necessary hydrationmaterial, and the circuit completed by applying the active electrode 54a to the medicament or medicament-containing substrate.

The first three stages of Herpes I and II are prodromal, erythema andpapule/edema. The preferred treatment with Acyclovir® is to identify andtreat the infection in its prodromal stage (no visible signs orsymptoms, but individuals feel a tingle or burning or some sensation inthe area that breaks out later), i.e., treat optimally with least amountof medicament and shortest application time. Erythema is second (stillquite early, with some redness and/or swelling) and is the preferredstage to start treatment if prodromal stage is missed. Papule or edemastage still responds to treatment but not as quickly (skin damage hasstarted to occur with small sores which may be barely visible).

In a preferred form of the present invention, particularly for thetreatment of Herpes I and II-type infections, Acyclovir®, is themedicament of choice. Acyclovir® may be provided in a cream formulationwith approximately 5% comprising the drug Acyclovir®. For example, a 250milligram formulation of topical cream containing 12.5 milligrams ofAcyclovir®, i.e., a 5% formulation, may be utilized. Significantly, thisrelatively small amount of medicament in the formulation, when appliedelectrokinetically over a predetermined time duration, affords atherapeutically effective dose. The dosage and time of application maybe varied. For example, an approximate 2% formulation of about 4 to 5milligrams of the active medicament (e.g., Acyclovir®) in a 250milligram cream formulation applied electrokinetically over a period ofno greater than fifteen minutes or an approximate 14-15% formulation,e.g., 37 milligrams in a 250 milligram cream and Acyclovir® formulation,applied electrokinetically for approximately three minutes is believedtherapeutically effective. Percentage formulations between 2%-15% overtime durations between fifteen minutes and three minutes are believedalso to be therapeutically effective. For example, 8%-10% formulationsover 5-6 minutes' time duration are also believed therapeuticallyeffective. Thus, using the present device and a small amount of theactive medicament applied electrokinetically and locally via the presentdelivery system has been found effective. While a cream formulation ispreferred, it will be appreciated that the topical base may also be aliquid, gel, ointment or lotion.

The formulation for the medicament may also comprise an oil, water, or acombination oil and water, to facilitate penetration of the skin as theexcipient(s). For example, oil facilitates penetration of the stratumcorneum layer of the skin, while water facilitates penetration of thebasal epidermal layer. Thus, a combination of the drug with oil andwater included in the formulation is preferred to facilitate penetrationof the drug to the treatment site. In a further formulation ofAcyclovir®, solvents such as methylene chloride or beta-cyclodextrin maybe included to improve water solubility and stability.

The foregoing treatment is also effective for treating Herpes Zoster,Cytomegalovirus (CMV) and additional medicaments of choice may includefoscarnet and gancilovir. The device and methods hereof may also be usedto provide electrokinetic transport, with or without ultrasound, fortamoxifen citrate, i.e., an antiestrogen, to inhibit Trans Growth Factor.beta.-1 (TGF.beta.-1) to suppress estrogen receptors to aid in woundhealing and treatment of keloid scar tissue. Also, treatment of eczemawith tacrolimus or pimecrolimus as a stand-alone therapy or withsteroids is effective. Still further, while Acyclovir® acts on thepolymerase enzyme, drug formulations which act on the helicase-primaseenzyme are also effective for treating Herpes I and II.

Referring now to FIGS. 44 and 45, there is illustrated a further form ofan electrokinetic delivery device according to a preferred embodiment ofthe present invention wherein like reference numerals are applied tolike parts, preceded by the numeral 1. In this form, the device 110includes proximal and distal portions 120 and 122, respectively, andcontacts 142 and 144 in the distal and proximal portions, respectively,for completing the electrical circuit as described herein. The proximalportion 120 includes loops 134 and tabs 136 on opposite sides forsecuring a strap to the proximal portion and securement of the device tothe individual's finger. The proximal portion 120 houses the electronicsand power source similarly as the proximal portion 20.

The distal portion 122 is generally frustoconically shaped, as is thedistal portion 22 of the prior embodiment, and mounts a pylon or a pairof pylons 123 interconnecting the frustoconical section 124 and theapplicator head 151 housing the substrate. The distal portion 122 alsocarries the counter electrode 160 which, upon interconnection of theproximal and distal portions is electrically connected to the powersource and electronics of the proximal portion 120. It will beappreciated that the undersurface of the proximal portion 120 is concaveand angled to accommodate the first finger joint and opposite sidesthereof for mounting the proximal portion on the individual's finger.Similarly, the distal portion 122 has a frustoconical interior surfacefor receiving the fingertip of the individual upon electrical andmechanical connection of the proximal and distal portions to oneanother. In FIG. 45, the device is illustrated in an operable conditionapplied to an individual's finger, with the individual's fingertipprojecting into the distal portion and in electrical contact with thecounter electrode 160.

FIG. 46 illustrates a block diagram of representative electricalcircuitry 200 for use in the finger splint medicator. Electricalcircuitry 200 includes an on/off flag 202, a power on/off switch 204, apower source 206, a switching regulator 208, processing circuitry(microprocessor) 210, a variable voltage source 212, a current clamp214, electrostatic discharge (ESD) protection circuits 216, a currenttransducer 218, and light emitting diode or diodes (LED's) 220. Theon/off flag 202 is built into the distal portion and may simply includea conducting “flag” surface which completes a circuit of the poweron/off switch 204 upon engaging to the proximal portion of the fingersplint medicator. The flag surface may, for example, be a thin (e.g.,0.032″ thick), copper-clad G10 board with copper on one side thereof.The power on/off switch may simply include two contacts connecting tothe power source 206 and to the remaining parts of electrical circuitry200.

Power source 206 is a battery such as a silver oxide battery having anopen-circuit voltage, for example, of 1.55V. The useful life of thebattery terminal voltage ranging from 1 to 1.55 V is insufficient tooperate circuit elements and components such as processing circuitry 210and LED's 220. The low battery voltage is tolerated due to thecompensation by switching regulator 208, which converts the unsteady anddecaying battery voltage to a constant value of, for example, 2.7V.

Skin and tissue resistance largely controls the bias potential requiredto sustain the treatment current. Other factors include the conductivityof medicament and the resistance between the skin and counter electrodeinterfaces. A typical range of overall resistance to be encountered isfrom 5 kohm to 80 kohm. In the most extreme case, a potential of over30V may be necessary. Variable voltage source 212 converts the lowbattery voltage to a suitable high output value controlled by a signalfrom processing circuitry 210. Measurements of the treatment currentfrom current transducer 218 are compared with a desired treatmentcurrent for the particular application to obtain an error signal.Processing circuitry 210 increases or decreases the control signal tothe variable voltage source 212 with an appropriate digital outputsignal to reduce and eliminate the measured error signal so as to obtainthe minimal necessary instantaneous bias potential for maintenance ofthe desired treatment current. Current clamp 214 is a redundant safetydevice used to limit the treatment current to a safe, maximum value(e.g., 450 microamps) under any circumstances.

Electro Static Discharge (ESD) protection circuits 216 (such as one ormore diodes) are installed at the entry points of the flag terminal andthe positive and negative treatment electrodes, respectively, to protectthe internal circuitry from electrostatic damage. The ESD protectioncircuit for the flag terminal is disposed on the proximal side.

Current transducer 218 converts the instantaneous treatment current toan analog voltage. This voltage is read by the processing circuitry 210through an internal analog-to-digital (A/D) converter. This digitalsignal is compared with the selected treatment current value scalable tothe reference input voltage of the A/D converter. A digital servo loopis maintained by the processing circuitry 210 to minimize and/oreliminate the error signal between the instantaneous treatment currentsignal and the current reference. The output of the servo loop is adigital signal converted by an R/C (Resistor/Capacitor) circuit to ananalog voltage, which is then used to control the variable voltagesource 212.

Processing circuitry 210 performs various tasks including, but notlimited to, timing control, current measurement, digital servo oftreatment current through feedback control of the bias potential, andillumination of LED or LED's. Processing circuitry 210 may beimplemented, for example, as a microprocessor, microcontroller, anapplication specific integrated circuit (ASIC), a programmable logicarray or some combination thereof.

Processing circuitry 210 includes read-only and/or read/write memory. Inone example implementation, processing circuitry 210 includes aread/write memory such as an EEPROM. The operations of processingcircuitry 210 may be implemented in hardware, software and/or firmware.It is desirable, although not necessary, to reduce and replace hardwareelements to the extent possible by using a firmware implementation. Dataand instructions for controlling the overall operation of thefinger-splint device may be written respectively, to an EEPROM datamemory and a flash program memory, and processing circuitry 210 mayexecute the instructions in response to various signals suppliedthereto. These instructions may include instructions for: monitoring thetreatment current and the battery terminal voltage, providing timingcontrol for various treatment phases including the initial standbyperiod (for example, indicated by a flashing green LED), soft-startperiod, main treatment period (indicated by a constant green LED) andthe final soft stop period (indicated by the red LED). The treatmentphases need not be the same for all treatments and these phases may varyin some way depending on what is being treated. All the variables,voltage, current, time, electrode size and shape, and the like must bereconsidered and possibly adjusted,

illuminating the LED(s) to provide information to the user,

exciting a crystal oscillator for accurate timing reference,

resetting a watchdog timer to ensure normal software execution,

performing a self-consistency check on the accuracy of analog-to-digitalconverter by measuring the predictable voltage drop across a circuitelement (such as an LED) during a short, initial power-up period, and

performing servo control of the treatment current by controlling thebias potential generated by the variable voltage source via an outputdigital signal.

The data stored by the read/write memory within the proximal portion mayalso include a count indicative of the number of treatment cycles forwhich the finger-splint device has been used. This count is incremented(or decremented) for each treatment and the device is permanentlydeactivated after the count reaches a prescribed number indicative of apredetermined number of treatments. For example, a disable flag fordisabling processing circuitry 210 may be set in memory when the counton the counter is indicative of the prescribed number of treatments.Alternatively or additionally, various mechanisms for preventing thesupply of power to the electrical components may be used to permanentlydeactivate the device. For example, processing circuitry 210 couldgenerate a signal to burn a fuse when the count on the counter isindicative of the prescribed number of treatments. Similarly, processingcircuitry 210 could generate a signal to deliberately damage atransistor or flip a solid state toggle circuit when the count on thecounter is indicative of the prescribed number of treatments. It will bereadily apparent that other mechanisms (hardware and/or software) may beused and the invention is not limited in this respect.

In another example implementation, the read/write memory may store atotal treatment time, which is incremented (or decremented) inaccordance with a timer during treatment. When the total treatment timereaches some prescribed total treatment time, the device may bepermanently deactivated. Here again, for example, the various hardwareand/or software disabling mechanisms described above may be used topermanently deactivate the device.

In still another example implementation, the proximal portion may bedisabled from use for a predetermined time period after each use wherebythe next use can only occur after the predetermined time period hasexpired. In this case, a disable flag could be set for the predeterminedtime period and processing circuitry 210 could prevent operation of theproximal portion when this flag is set.

Also, the distal portion may be deactivated permanently after a singleusage. Here again, various mechanisms for prevention of re-use of thedistal portion may be used. For example, processing circuitry 210 couldgenerate a signal to burn a fuse incorporated in the distal portion atthe end of a treatment. Similarly, processing circuitry 210 couldgenerate a signal to deliberately damage a transistor or flip a solidstate toggle circuit incorporated in the distal portion at the end of atreatment. It will be readily apparent that other mechanisms (hardwareand/or software) may be used and the invention is not limited in thisrespect.

Processing circuitry 210 may be programmed with (or have accessiblethereto) instructions for a plurality of different types of treatments(e.g., herpes, eczema, acne, boils, blemishes and the like). Forexample, the desired treatment current, ramp-up/ramp downcharacteristics and total treatment time for herpes may be differentthan the desired treatment current, ramp-up/ramp-down characteristicsand total treatment time for eczema. The determination of whichinstructions to use may be based upon a detection (or “recognition”) ofa particular type of distal portion attached thereto. For example, adistal portion for the treatment of herpes may be configured (eitherphysically or electrically) differently than the distal portion for thetreatment of eczema. The configuration of the distal portion isdetectable by processing circuitry 210 so that processing circuitry 210thereafter executes instructions appropriate for the particular type ofdistal portion connected thereto.

In another implementation, the distal portion may be provided with aninterface for interfacing to a computer. Such an interface may, forexample, be a serial port, a parallel port, a USB port, an IEEE 1394port, etc. The interface may take the form of a cradle or dockingstation into which the distal portion is placed, the cradle or dockingstation connecting to the computer. The interface to a computer allowsthe uploading and downloading of data from/to the distal portion. Forexample, a physician, pharmacist or other health care provider coulddownload to the distal portion instructions appropriate for a particulartreatment. Alternatively, an appropriate one of a plurality ofdifferent, pre-programmed instruction sets may be selected. Processingcircuitry 210 may be programmed to record in memory treatmentinformation (such as the time a treatment took place, the duration ofthe treatment, the distal portion type connected thereto, etc.). Thisrecorded information may be uploaded to a database containing treatmentrecords for the user via the computer interface.

Assuming appropriate power is available, the distal and/or proximalportion may be provided with additional elements. For example, a smallliquid crystal display (LCD) could be provided to the distal or proximalportion to provide a visual output of timing and/or diagnostics. Soundgenerating circuitry such as a buzzer may also be added to provide auralindications such as warnings, end-of-treatment, etc.

FIG. 47 is a schematic showing details of example electrical circuitry200. Battery 300 corresponds to power source 206 (FIG. 46) and may, forexample, have an open-circuit voltage of 1.55V and a rated capacity of200 mAhr. A suitable battery may be, but is not limited to, EPX76 1.5Vsilver oxide battery (designation: IEC SR44) available from EvereadyBattery Co., Inc. Such a battery would provide for about 10 treatmentsessions, if each were ten minutes in length.

Components U1, L1, D1, C1 and C2 correspond to switching regulator 208(FIG. 46) for converting the battery voltage to a constant value of, forexample, 2.7 V. U1 may be, but is not limited to, an NCP1402SN27T1step-up DC-DC converter (TSOP-5) available from On Semiconductor, Inc.L1 may be, but is not limited to, ELJ-EA470KF, 47 microhemy inductor(SMT-1210) available from Panasonic Industrial Co. D1 may be, but is notlimited to, an RB751V40T1 Schottky barrier diode (SOD-323) availablefrom On Semiconductor Inc. C1 and C2 may be, but are not limited to, a22 microfarad, 4V tantalum capacitor (A case) and a 47 microfarad, 4Vtantalum capacitor (B case), respectively.

Component U4 corresponds to processing circuitry 210 and may be, but isnot limited to, a PIC16F85 microcontroller (SSOP-20) available fromMicrochip Technology Inc.

Components U2, L2, D2 and C3 function as variable voltage source 212(FIG. 46) for converting the low battery voltage to a high output value.U2 may be, but is not limited to, an S-8324D20MC switching regulator(SOT-23-5) available from Seiko Instruments USA. L2 may be, but is notlimited to, an ELJ-EA101KF, 100 microhenry inductor available fromPanasonic industrial Co. D2 may be, but is not limited to, an MBRO540T1Schottky barrier diode (SOD-123) available from On Semiconductor Inc. C3may be, but is not limited to, a 1 microfarad ceramic capacitor (50V,Y5V, SMT-1206). Variable voltage source 212 is controlled in accordancewith a signal from processing circuitry 210. Based on measurements ofthe treatment current, processing circuitry 210 calculates anappropriate digital output signal to obtain an instantaneous biaspotential. Component R4 coupled with C4 functions as a simpledigital-to-analog converter. R4 may be, but is not limited to, a 10Kohm, 1% metal film resistor (SMT-0603). C4 may be, but is not limitedto, a 0.1 microfarad ceramic capacitor (10V, X7R, SMT-0402).

Components U3 and R2 correspond to current clamp 214 (FIG. 46) and limitthe treatment current to a maximum, safe value such as, for example, 450microamps. U3 may be, but is not limited to, an LM334M current source(SO-8) available from National Semiconductor Corp. R2 may be, but is notlimited to, a 150 ohm, 1% metal film resistor (SMT-0603).

D3, D7 and D8 correspond to (ESD) protection circuits 216 (FIG. 46) andD3 comprises 36 V bi-directional voltage suppressor (TVS), which isinstalled at the positive electrode. This TVS protects internalcircuitry from electrostatic damage. D3 may be, but is not limited to,an SMAJ36CA transient voltage suppressor (SMA) available from DiodesInc. D7 and D8 may be, but are not limited to, a PSD03C 3.3V transientvoltage suppressors (SOD-323) available from ProTek Devices.

R5 corresponds to current transducer 218 (FIG. 46) and converts thetreatment current to an analog voltage, which is further stabilized byC5. R5 may be, but is not limited to, a 4.99 Kohm, 1% metal filmresistor (SMT-0603). C5 may be, but is not limited to, a 0.47 microfaradceramic capacitor (50V, Z5U, SMT-0805). Green LED D6 and red LED D5correspond to LEDs 220. Suitable LED's include, but are not limited to,a green diffused LED and a red diffused LED available from AmericanBright Optoelectronics Corp. (BL-B22131 and BL-B4531). Green LED D6remains on during the entire treatment period. The LED normally requiresa current limiting resistor for its operation and the resulting powerconsumption is quite substantial. As shown in FIG. 47, a capacitor C8switched in accordance with U5 operates as an efficient current limitingdevice. The situation with red LED D5 is different in that on the rareoccasions when it is illuminated, the treatment current is switched offand resistor R3 and the resulting power consumption can be tolerated. U5may be, but is not limited to, an Si1905DL dual P-channel MOSFET(SC-70-6) available from Vishay Intertechnology Inc.

The electronic circuitry described in connection with FIGS. 46 and 47 isoperable so that the finger-splint electrokinetic medicator provides acontrolled current for electrokinetically transporting medicament intothe treatment site and into the underlying tissue area. The disclosedelectronic circuitry provides an effective therapeutic for a skin lesionby incorporating the following features:

the treatment current is increased and decreased gradually to avoid anyuncomfortable sensation of electrical shock, the rise and fall ofcurrent may follow a linear ramp or an exponential curve with a longtime constant, (e.g., 10 seconds),

the treatment current per application is accurately controlled byautomatic feedback, e.g., maintained at 0.4 milliamperes or less,

an upper limit of the treatment current is imposed by a stand-byredundant circuit element in order to safeguard against servo loopmalfunction,

minimal bias potential, dictated largely by patient skin resistance, isalways applied in order to minimize power consumption,

ESD protection is implemented for electronic circuitry,

indicator light(s) are provided for low battery conditions, diagnostics,hardware malfunction, low treatment current, and test completion,therapeutic phase,

the prescribed treatment time period and automatic test termination areaccurately controlled, and

treatment history is monitored and the device is permanently deactivatedafter reaching a prescribed length of time and/or number of treatmentsor uses.

The circuit described in connection with FIGS. 46 and 47 provide theseidentified features. However, the present invention is not intended tobe limited to only circuits that provide for all these features. Inaddition, it will be appreciated that the specific components and thearrangements thereof shown in FIGS. 46 and 47 are provided by way ofexample, not limitation. For example, power source 300 may be an adapterfor converting power from a conventional wall outlet to power suitablefor operation of the finger splint. Alternatively, power source 300 maybe a battery that is rechargeable via an adapter connected to aconventional wall outlet. In addition, the electronic circuitry may beadapted to include an alternating current source as described inapplication Ser. No. 09/523,217, filed on Mar. 10, 2000, the contents ofwhich are incorporated herein by reference, including the hybridmulti-channel design. In still other alternative implementations, thepower source may be provided in the distal portion or the distal portionmay be provided with a power source to supplement the power source inthe proximal portion.

FIGS. 54A and 54B are flow charts illustrating an example operation ofthe device 10. At step 502, the distal portion 22 is engaged with theproximal portion 20 and power is turned on at step 504 when flag surface202 completes the circuit of the power on/off switch 204. Processingcircuitry 210 performs a battery test operation (step 506) to determineif the battery is okay. If not, the red LED is flashed for apredetermined period of time (e.g., one minute) (step 508) and the poweris then switched off (step 510). If the battery is okay, processingcircuitry 210 determines whether the number of uses of the proximalportion is less than a prescribed number of uses. If not, the red LED isflashed for a predetermined period of time (step 508) and the power isthen switched off (step 510).

If the number of uses is less than the prescribed number, the green LEDis flashed for a predetermined period of time (e.g., 10 seconds) (steps514 and 516). Then, processing circuitry 210 begins to ramp up thetreatment current (step 518). After the treatment current is ramped up,treatment begins. During treatment, processing circuitry 210 checks todetermine whether the current is greater than 360 microamps. If not, thegreen LED is flashed (step 522) and the processing circuitry proceeds tothe battery test operation (step 526). If the current is greater than360 microamps, the green LED is kept on (step 524) before proceeding tothe battery test operation.

If the battery fails the battery test operation, the red LED is flashedfor a predetermined period of time (step 508) and then the power isswitched off (step 510). If the battery is okay, processing circuitry210 determines whether the treatment time period (e.g., 10 minutes) haselapsed. If not, control returns to step 520. If the treatment timeperiod has elapsed, the ramp down of the treatment current begins andthe green LED is kept on (step 530). When processing circuitrydetermines that the treatment current has decreased below 50 microamps(step 532), the red LED is turned on (step 534) and kept on for apredetermined period of time (e.g., one minute) (step 536). After thispredetermined period of time, the red LED is turned off and thetreatment number is incremented (step 538). After a predetermined periodof time elapses (e.g., 4 hours) (step 540), the power is switched off(step 542).

FIG. 54B shows the treatment current servo loop which is executed almostcontinuously throughout the treatment. At step 560, the treatmentcurrent is sampled and converted from an analog value to a digitalvalue. At step 562, a determination is made as to whether the sampledtreatment current is equal to the reference treatment current for thecurrent treatment. If so, control returns to step 560 where thetreatment current is sampled again.

If the sampled treatment current is not equal to the reference currentat step 562, a determination is made at step 564 as to whether thetreatment current is greater than the reference current. If so, thecontrol data output of the processing circuit is decreased and thisoutput is converted from a digital value to an analog value at step 568.If the treatment is not greater than the reference current, adetermination is made at step 570 as to whether the treatment current isless than the reference current. If so, the control data output of theprocessing circuit is increased and this output is converted from adigital value to an analog value at step 568.

When using the device 10, 110 hereof, the individual may apply theproximal portion 20, 120 in overlying relation to a finger, preferablythe index finger, to be used to apply the medicament to the treatmentsite. Thus, the proximal portion 20, 120 is overlaid outside portions ofthe individuals' finger, straddling opposite sides of the first knucklejoint and secured thereto by straps 14, 114. The substrate 56, 156 ispreferably prepackaged with a unit dose of medicament and suppliedwithin the applicator head of the distal portion 22, 122. If not, thesubstrate may be applied to the recess 52, 152 of the applicator head onthe distal portion 22, 122 of device 10, 110 with or without themedicament. Particularly, the substrate 56, 156 may be inserted into therecess 52, 152 such that the medicament or hydration material within thesubstrate makes electrical contact with the active electrode 54, 154. Ifthe medicament is electrokinetically transportable and contained in thesubstrate, the device is ready for use upon connecting the distalportion 22, 122 with the proximal portion 20, 120. Alternatively, if themedicament is not permeated within the substrate, the individual mayapply the medicament to the substrate or over the treatment site withsuitable hydration material being applied as necessary or desired.Alternatively, if the medicament is provided in a releasable orrupturable capsule in the substrate, the individual may apply pressureto the substrate in the applicator head, rupturing the capsule, enablingthe medicament from the capsule to permeate through the open intersticesof the porous substrate. If the medicament is not iontophoreticallytransportable, the substrate may be hydrated by applying water or salineto the substrate.

Once the medicament is enabled for electrokinetic transport, thefrustoconical section 40, 140 of the distal portion 22, 122 may bereceived about the individual's fingertip and contact made with theproximal portion by interconnecting the contacts 42, 142 and 44, 144. Byapplying the distal portion 22, 122 to the proximal portion 20, 120 andupon application of the applicator head to the treatment site, theelectrical circuit is completed. Thus, the electrical circuit includesthe active electrode 54, 154, the medicament or the hydration materialused to electrokinetically transport the medicament, the treatment site,the individual's body, a return through the counter electrode, the powersource and electronics to the active electrode 54, 154.

A treatment program may comprise one or more applications of medicamentto a treatment site using the finger splint device described above. Forexample, a treatment program may comprise five applications ofmedicament. After each application of medicament, the disposable distalportion is removed from the proximal portion, and a new distal portionis connected to the (re-usable) proximal portion prior to the nextapplication. In some instances, it may be desirable to vary the amountand/or efficacy of the medicament from one application to the next. Forexample, the amount of medicament used for the first application may begreater than the amount of medicament used for some subsequentapplication. Thus, a user of the finger splint device may purchase atreatment “package” comprising a plurality of distal portions (e.g., oneor more having different amounts of medicament) to be used in apredetermined order. The distal portions may be configured electricallyand/or mechanically in a manner that permits the processing circuitry ofthe proximal portion to detect which distal portion is connectedthereto. By way of example, not limitation, the distal portion mayinclude registers readable by the proximal portion. The registers mayinclude information such as, but not limited to, the number of thatdistal portion in a particular order of use of distal portions. If theprocessing circuitry is programmed to track the medicament applications(e.g., by incrementing a hardware or software counter as each medicamentapplication is completed), the proximal portion can inform the user(e.g., via the red LED or some other output device such as an LCD ifprovided) when a wrong distal portion (e.g., an out-of-sequence distalportion) is connected thereto. The detection of the distal portionconnected thereto can also be used by the processing circuitry to set atimer fixing an amount of time that must pass before the next medicamentapplication. The proximal portion is disabled to prohibit its use untilthis time period elapses.

In addition, it will be appreciated that the same proximal portion maybe used with more than one type of distal portion. Thus, for example,the proximal portion may be selectively connected to one type of distalportion containing medicament for use in the treatment of herpes or toanother type of distal portion containing medicament for use in thetreatment of eczema. These distal portions may be configuredelectrically and/or mechanically so that the processing circuitry of theproximal portion can detect the type of distal portion connectedthereto. In response to this detection, the proximal portion can, forexample, use operating instructions suitable for a medicamentapplication using the distal portion connected thereto.

The processing circuitry of the proximal portion may be programmed with(or have accessible thereto, e.g., via a memory) a plurality ofdifferent treatment current profiles (treatment current versus time),wherein the treatment current profile that is actually used depends uponthe distal portion connected thereto. For example, in the case in whicha treatment program comprises a plurality of applications of medicament,the treatment current profile for the first medicament application maybe different than the treatment current profile for the last medicamentapplication. Similarly, the treatment current profile for a herpestreatment program may be different than the treatment current profilefor an eczema treatment program. Here again, the distal portions may beconfigured electrically and/or mechanically (e.g., using registers onthe distal portion) in a manner that permits the processing circuitry ofthe proximal portion to detect which distal portion is connectedthereto. In this way, the processing circuitry can use the treatmentcurrent profile appropriate for the proximal portion connected thereto.

Referring now to FIG. 48, there is illustrated a further embodiment of adevice for electrokinetically transporting a medicament into the skinand is particularly useful for applying medicament over large wide areasof an individual's face. For example, the illustrated mask, generallydesignated 150, may be used to treat dermatological conditions, e.g.,eczema, psoriasis acne, boils, blemishes, provide anesthesia, or toprovide dermal exfoliation. Treatment for wrinkles may be accomplishedby delivering a modulator of collagen deposition, an organic nitrate,e.g., gallium nitrate. Treatment with metronidazole for rosecea is alsobeneficial. In this form of the present invention, there may be provideda full face mask 155 (FIG. 48) or a partial face mask 154 (FIG. 47). Theface masks 152 and 154 may be formed of a matrix, e.g., a plastic orfabric material, which may be flexible for providing contact between anunderlying medicament-carrying substrate 156. The underlying substrate156 is formed of a porous material similarly as the substratespreviously discussed. The porous material preferably has honeycomb cellswhich divide the substrate laterally to minimize lateral disbursement ofthe medicament contained in the substrate.

An electrical connector 158 carried by the mask connects an electricalpower source to the mask via a plurality of independent or isolatedelectrical current channels or lead wires 160 carried by the matrix toform individual electrical conductive channels in the matrix. Thecurrent flowing through the channels is separately controlled to preventtunneling of the current which would adversely affect the user.

The face mask is preferably portable, although it will be appreciatedthat the power supply can be provided either by an adapter plugged intoa conventional electrical current supply or a “tabletop” or “portable”type unit with batteries that may be either disposable or rechargeable.Preferably, however, the power supply may be disposed in a housingportion 162 which corresponds in functionality to the electronics andpower source contained in the proximal portion previously discussed.Additionally, another housing portion 164 is adapted for releasablycoupling with the portion 162. As in the prior embodiments, connectionof housing portions 162 and 164 activates the device. Portions 162 and164 may serve, in effect, as an on/off switch for activating the device.As illustrated, the proximal portion 162 is electrically coupled toanother portion of the face mask through a counter electrode 166. Itwill be appreciated, however, that the counter electrode 166 may beapplied to other parts of the individual's body to complete theelectrical circuit. For example, the counter electrode 166 may extendabout the periphery of the mask 155 in contact with the individual'sskin.

To utilize the electrokinetic device in the form of a face mask, theuser dons the mask and attaches the mask to overlie the skin surface onthe face by securing straps 170 about the back of the head. It will beappreciated that the substrate contains the medicament to be appliedelectrokinetically to the individual's face and thus lies inregistration with the individual's face. Also note that the electricalconductors or electrodes 160 are closely spaced relative to one anotherto provide broad coverage, only a small number of the electrodes 160being illustrated for clarity. Consequently, with the face mask appliedas illustrated, the user couples the distal and proximal portions 164and 162, respectively, to one another, completing the circuit from thepower source, through the distal portion, the electrical conductors 160which electrokinetically motivate the medicament into the facial skin,and the counter electrode for return to the power source. Alternatively,the coupling of the distal and proximal portions may enable the circuit,provided an on/off switch in the circuit is turned “on.” A multi-channelsystem is provided in the face mask and particulars of the multi-channelsystem are disclosed in U.S. Pat. No. 5,160,316, issued Nov., 3, 1992,the disclosure of which is incorporated herein by reference.

In FIG. 49, like parts as in FIG. 48 are designated by like referencenumerals followed by the suffix “a”. The mask 155 is abbreviated fromthat illustrated in FIG. 48 and overlies facial regions about the eyesand nose of the individual and may cover substantially the entireforehead and portions of the cheeks or possibly include the neck or be aseparate specific neck treatment applicator. The electromechanicalelements of the embodiment are similar to those of FIG. 48 and includethe underlying medicament carrying porous substrate 156 a, electricalconnector 158 a, lead wires 160 a, proximal and distal portions 162 aand 164 a, respectively, and a counter electrode 166 a. Thefunctionality of these elements is the same as in the previousembodiment.

In a further embodiment of the present invention, there is illustratedwith reference to FIGS. 50 and 51 a finger-mounted electrokineticdelivery device, generally designated 200, for the self-administrationof a medicament and generally in the form of a ring carried by orapplied about an individual's finger, preferably the index finger. Ring200 includes a body 202. The generally ring-shaped body 202 has athrough-opening 204 to receive the individual's finger and which openingis flanked by a pair of arcuate sections 206 which, together with a topportion of body 202, form a split ring for maintaining the device 200 onthe individuals finger. It will be appreciated, of course, that body 202may comprise a full circular ring without interruption, although thesplit ring form is believed preferable to provide flexibility and toaccommodate different finger sizes.

The device 200 is self-contained and thus includes within the body 202 apower source 208 and electronics 210, as well as electrical connections212 and 214 for electrically connecting the power source and electronicsto an active electrode 216 and a counter electrode 218, respectively.The power source 208 and electronics 210 are similar to those describedpreviously in the prior embodiments. The active electrode 216 may be inthe form of a disk disposed in a recess 220, preferably circular, alongthe flat outer surface 222 of the ring-shaped body. Overlying the activeelectrode 216 and in contact therewith is a corresponding generallycircular substrate 224 having the same attributes as the substrates 56,156 previously described. Substrate 224 is maintained on the body 202 bya cap 226 secured to the flat outer surface 222 of the body and havingmarginal portions 228 overlying margins of the substrate 224. As in theprior embodiments, the substrate 224 contains a unit dose of medicament,and hydration material, if necessary, prepackaged with the device 200for one-time disposable use. Alternatively, the substrate 224 may beseparately packaged with a unit dose of medicament and hydrationmaterial, if necessary, apart from device 200 and applied to the device200 and removed therefrom for each use whereby the device 200 may bereused with successive one-time use prepackaged substrates withmedicament. As in previous embodiments, the outer contact surface of thesubstrate which is to be applied to the treatment site may be overlaidwith a foil or releasable film, e.g., as illustrated in FIG. 42, toprotect the contact surface and medicament prior to use.

The counter electrode 218 is preferably formed along the inside concavesurface of the ring-shaped device 200. It will be appreciated that uponapplying the ring-shaped body 202 to the individual's finger, thecounter electrode 218 will automatically lie in electrical contact withthe individual's finger. That is, the flexible side sections 206 of thedevice 200 bias the body 202 such that counter electrode 218 is pressedagainst the individual's finger. As illustrated in FIG. 51, the red andgreen LED's are indicated 230 and 232 along one side of the device toafford the indications described previously.

To use the device, the ring is disposed about the individual's finger.The device 200 may be provided with an on/off switch to enable thecircuit between the active and counter electrodes and through theindividuals body. Alternatively, the circuit may be activated inresponse to application of the ring-shaped body about the individual'sfinger. For example, the counter electrode 218 may be movable from anoutwardly exposed position within the opening 204 to a position lyingflush with the interior surface of the ring-shaped body 202 and whichmovement completes the internal circuit within the body 200 between theactive and counter electrodes. With the ring mounted on an individual'sfinger, it will be appreciated that the substrate can be disposed over atreatment site which completes the electrical circuit through theindividual's body and enables electrokinetic transport of the medicamentinto the treatment site. At the end of the treatment period, the devicemay be removed from the individual's finger and discarded in itsentirety. Alternatively, the device is removed from the individual'sfinger and substrate may be removed from the ring and replaced by afresh medicament-containing substrate for subsequent treatment. Ofcourse, if reuse of the device with a fresh substrate is indicated, theon/off switch is placed in the “off” condition or the circuit may beinterrupted automatically upon removal of the device from theindividuals finger and return of the counter electrode 218 to itsprojecting position within the opening 204.

FIGS. 52 and 53 are a bottom view and a side perspective view,respectively, of a patch applicator 300. The patch applicator isintended for limited (one- or two-time) use, after which it is disposed.Patch applicator 300 includes an active electrode 302 and a counterelectrode 304. Embedded within the applicator body 306 are a battery308, a switch 310 and an ASIC 312. Optionally, an LED may be provided.Switch 310 may be a touch-sensitive switch (e.g., membrane) so that theuser's finger applied to the counter electrode 304 to hold theapplicator in place at the treatment site activates the patchapplicator. ASIC 312 controls the treatment current, treatment time,etc. as appropriate for the treatment for which the patch applicator isintended. The optional LED may be illuminated to provide a visualindication that the patch applicator is activated. Alternatively, anon-ultrasound generated vibration can be added or used in lieu of theLED to indicate a working status of the device and that the device liesin a closed current loop via the individuals body surface.

While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiment,it is to be understood that invention is not to be limited to thedisclosed embodiment, but on the contrary, is intended to cover variousthe modifications and equivalent arrangements included within the spiritand scope of the appended claims.

1. A method of treating a fungal infection of the nail of an individual,the method comprising: applying a device to at least one nail of theindividual that is infected by a fungus, wherein the device includes atleast one active electrode and at least one counter electrode, whereinthe at least one counter electrode is in contact with the individual,and wherein the device is connected to at least one power source;disposing an anti-fungal medicament between the at least one activeelectrode and the at least one nail of the individual infected by afungus; and providing an electrical current from the power source to theat least one active electrode to facilitate delivery of the anti-fungalmedicament into the region of the at least one nail.
 2. The method ofclaim 1, wherein the medicament is contained within a pad.
 3. The methodof claim 1, wherein the medicament comprises a conductive fluid.
 4. Themethod of claim 1, wherein the nail is a toenail.
 5. The method of claim1, wherein the medicament is delivered directly into the nail bed. 6.The method of claim 1, wherein the medicament is delivered into the nailbed and surrounding nail tissue.
 7. A device for delivery of a substanceto a treatment site on an individual, comprising: a power supply; anapplicator including a first electrode and a pad for containing asubstance, wherein the first electrode is connected to the power supplyand the pad is positioned on a first side of the applicator with thefirst electrode overlying the pad; and a second electrode connected tothe power supply; wherein, upon application of the applicator againstthe treatment site and the second electrode in contact with a portion ofthe individual's body, an electrical circuit is completed between thefirst electrode through the treatment site, the portion of theindividual's body and the second electrode for electrokineticallydriving the substance into the treatment site.
 8. The device of claim 7,wherein the substance is an anti-fungal agent.
 9. The device of claim 7,wherein the substance comprises a conductive fluid.
 10. The device ofclaim 7, wherein the treatment site is a nail.
 11. The device of claim10, wherein the nail is a toenail.
 12. The device of claim 10, whereinthe medicament is delivered directly into the nailbed.
 13. The device ofclaim 10, wherein the medicament is delivered into the nail bed andsurrounding nail tissue.
 14. A system for delivering a substance to aninfected nail of an individual, comprising: a power source; a deviceconnected to the power source, the device comprising at least one activeelectrode and at least one counter electrode, wherein the at least onecounter electrode is in contact with the individual; and a medicamentdisposed between the at least one active electrode of the device and theinfected nail of the individual; wherein an electrical current isprovided from the power source to the at least one active electrode toelectrokinetically drive the medicament into the region of the infectednail.
 15. The system of claim 14, wherein the substance is ananti-fungal agent.
 16. The system of claim 14, wherein the substance iscontained within a pad.
 17. The system of claim 14, wherein thesubstance comprises a conductive fluid.
 18. The system of claim 14,wherein the nail is a toenail.
 19. The system of claim 14, wherein thesubstance is delivered directly into the nail bed.
 20. The system ofclaim 14, wherein the substance is delivered into the nail bed andsurrounding nail tissue.